Amino acid analog CCK antagonists

ABSTRACT

Analogs of CCK-tetrapeptides, which analogs have the formula ##STR1## wherein A, B, D, R 1 , R 2 , R 3 , and R 4  are specifically defined, having activity as CCK antagonists, useful in the treatment or prevention of disorders of the gastrointestinal, central nervous, appetite regulating or pain regulating systems.

This is a continuation-in-part of U.S. patent application Ser. No.793,414, filed Jun. 26, 1990 now abandoned, originally filed through thePCT as patent application Ser. No. PCT/US90/03630, which is acontinuation-in-part of U.S. patent application Ser. No. 582,896 filedApr. 4, 1989, now abandoned, which is a continuation-in-part of U.S.patent application Ser. No. 376,778, filed Jul. 7, 1989, now abandonedoriginally filed through the PCT as patent application Ser. No.PCT/US89/01412, filed Apr. 4, 1989, which is a continuation-in-part ofU.S. patent application Ser. No. 177,715, filed Apr. 5, 1988, nowabandoned.

TECHNICAL FIELD

The present invention relates to compounds and compositions whichantagonize cholecystokinin and gastrin, processes for making suchcompounds, synthetic intermediates employed in these processes and amethod for treating gastrointestinal disorders, central nervous systemdisorders, cancers of the gastrointestinal system (i.e., pancreas, gallbladder, etc.), hypoinsulinemia, or potentiating analgesics, orregulating appetite disorders with such compounds.

BACKGROUND OF THE INVENTION

Cholecystokinins (CCK) are a family of polypeptide hormones. CCK and a33 amino acid fragment of CCK (CCK₃₃) were first isolated from hogintestine. (Mutt and Jorpes, Biochem. J., 125,628, 1981). Recently theCCK₃₃ fragment has been found in the brain, where it appears to be theprecursor of two smaller fragments, an octapeptide CCK₈ and atetrapeptide CCK₄ (Dockray, Nature, 264, 4022, 1979).

CCK₈, the carboxyl terminal octapeptide fragment of CCK, is the smallestCCK fragment that remains fully biologically-active. (Larsson andRehfeld, Brain Res. 165,201-218, 1979). The localization of CCKfragments in the cortex of the brain suggests that CCK may be animportant neuromodulator of memory, learning and control of primarysensory and motor functions. CCK and its fragments are believed to playan important role in appetite regulation and satiety. (Della-Fera,Science. 206,471, 1979; Gibbs et al., Nature, 289, 599, 1981; and Smith,Eating and Its Disorders, Raven Press, New York, p. 67, 1984).

CCK antagonists (B. J. Gertz in Neurology and Neurobiology, Vol 47,Cholecystokinin Antagonists, Wang and Schoenfeld, eds., Alan R. Liss,Inc., New York, N.Y., pp. 327-342, 1988; Silverman et al., Am JGastroent, 82(8), 703-8, 1987) are useful in the treatment andprevention of CCK-related disorders of the gastrointestinal (GI) (Lottiet al., J. Pharm Exp Therap, 241(1), 103-9, 1987), central nervous (CNS)(Panerai et al., Neuropharmacology, 26(9), 1285-87, 1987) and appetiteregulatory systems of animals, especially man. CCK antagonists are alsouseful in potentiating and prolonging opiate induced analgesia and thushave utility in the treatment of pain. (Faris et al., Science 226, 1215,1984; Rovati et al., Clinical Research, 34(2), 406A, 1986; Dourish etal., European J. Pharmacology, 147, 469-72, 1988). Disease states thatmay be treated with CCK antagonists are disorders of gastric emptying,gastroesophageal reflux disease (Setnikar et al, Arzn Forsch./DrugResearch, 37(II) 10, 1168-71, 1987), pancreatitis, pancreatic andgastric carcinomas (Douglas et al., Gastroent, 96, 4629, 1989; Beauchampet al., Am Surg. 202, 313-9, 1985), disorders of bowel motility, biliarydyskinesia, anorexia nervosa, hypoglycemia (Rossetti, Diabetes, 36,1212-15, 1987; Reagan, European J. Pharmacology, 144, 241-3, 1987),gallbladder disease, and the like.

Previously four distinct chemical classes of CCK receptor antagonistshave been reported. The first class comprises derivatives of cyclicnucleotides as represented by dibutyryl cyclic GMP (Barlos et al., Am,J. Physiol., 242, G161, 1982) and references sited therein). The secondclass is represented by the C-terminal fragments of CCK (see Jensen etal., Biochem. Biophys. Acta, 757, 250 1983) and Spanarkel, J. Biol.Chem. 258, 6746, 1983). The third class comprises amino acid derivativesof glutamic acid and tryptophan as indicated by proglumide (and itsanalogs) and benzotript, very simple analogs of CCK (see Hahne et al.,Proc. Natl. Acad, Sci. U.S.A., 78, 6304, 1981 and Jensen et al.,Biochem. Biophys. Acta. 761,269, 1983). The fourth and most recent classis comprised of 3-substituted benzodiazepines, represented by L-364,718(see: Evans et al., Proc. Natl, Acad, Sci, U.S.A., 83 4918, 1986).

With the exception of certain substituted benzodiazepines and recentlyreported analogs of proglumide (Makovec et al., Arzneim.-Forsch./DrugRes. 36,(I), 98-102, 1986; European Patent Application No. 0,272,228;PCT Patent Application No. WO 88/05774), all of these compounds arerelatively weak antagonists of CCK usually demonstrating IC₅₀ 's between10⁻⁴ and 10⁻⁶ M. The benzodiazepine CCK antagonists or their metabolitesmay have undesirable effects in vivo due to their interaction withbenzodiazepine or other receptors.

The C-terminal pentapeptide fragment of CCK is the same as theC-terminal pentapeptide fragment of another polypeptide hormone, gastrinGastrin, like CCK, exists in the GI system. Gastrin antagonists areuseful in the treatment and prevention of gastrin related disorders ofthe GI system such as ulcers, Zollinger-Ellison syndrome and central Gcell hyperplasia. There are no effective receptor antagonists of the invivo effects of gastrin. (Morely, Gut Pept. Ulcer Proc., Hiroshima Symp.2nd, 1, 1983). A recent report (Bock J. Med. Chem., 32, 13-16, 1989)discloses potent in vitro gastrin antagonists.

Analogs of proglumide have also been disclosed by Freidinger (U.S. Pat.4,860,938) and Nadzan and Kerwin (U.S. Pat. No. 4,971,978), but bothrequire a carboxylate or carboxyalkyl terminal group, respectively, andneither possesses the novel combinations of activity and selectivity ofthe instant invention.

DISCLOSURE OF THE INVENTION

In accordance with the present invention, there are cholecystokininantagonists of the formula: ##STR2## or a pharmaceutically-acceptablesalt, ester or amide thereof, wherein: A is aryl, as defined below;substituted aryl, as defined below; heteroaryl, as defined below; orsubstituted heteroaryl, as defined below;

B is absent, or is O, N, S, ethylene, or substituted ethylene, asdefined below;

R¹ is hydrogen or C₁ -C₃ -alkyl, as defined below;

R² is:

(1) hydrogen,

(2) aryl-C₁ -C₃ -alkyl, or

(3) when R³ is hydrogen, additionally C₁ -C₆ -alkyl, as defined below,C₃ -C₇ -cycloalkyl, as defined below, or C₂ -C₆ -alkenyl, as definedbelow; or

R² and D are linked together with the atoms to which they are attachedto form:

(a)--C₄ -C₇ -alkylene, as defined below, or

(b) --(CH₂)_(q) --G--(CH₂)_(q) --, wherein q is independently 1, 2 or 3at each occurrence and G is O or S;

D is selected from the group consisting of:

(1) hydrogen,

(2) C₁ -C₆ -alkyl,

(3) C₂ -C₆ -alkenyl,

(4) C₃ -C₇ -cycloalkyl,

(5) aryl,

(6) substituted aryl,

(7) Het, as defined below,

(8) substituted Het, as defined below,

(9) aryl-C₁ -C₆ -alkyl-, as defined below,

(10) Het-C₁ -C₆ -alkyl-, as defined below,

(11) substituted Het-C₁ -C₆ -alkyl-, as defined below,

(12) aryl-(mono-substituted-C₁ -C₆ -alkyl)-, as defined below,

(13) Het-(mono-substituted-C₁ -C₆ -alkyl)-, as defined below,

(14) R⁶ --O--C₁ -C₆ -alkyl-, wherein: R⁶ is:

(i) hydrogen,

(ii) C₁ -C₆ -alkyl,

(iii) aryl-C₁ -C₆ -alkyl-,

(iv) substituted aryl-C₁ -C₆ -alkyl-, as defined below, or

(v) R⁷ --E--C(O)--, wherein: R⁷ is:

(a) C₁ -C₆ -alkyl,

(b) aryl,

(c) substituted aryl,

(d) Het,

(e) aryl-C₁ -C₆ -alkyl-,

(f) substituted aryl-C₁ -C₆ -alkyl-, or

(g) Het-C₁ -C₆ -alkyl-; or

when E is N--R⁸, as defined below, R⁷ and R⁸ may be linked together withthe atoms to which they are attached to form N--C₄ -C₇ -alkylene orN--(CH₂)_(q) --G--(CH₂)_(q) --, wherein q and G are as defined above;and

E is absent, O, or N--R⁸, wherein: R⁸ is:

(a) hydrogen,

(b) C₁ -C₆ alkyl,

(c) aryl,

(d) substituted aryl, or

(e) aryl-C₁ -C₆ -alkyl-; or

when E is N--R⁸, additionally R⁷ and R⁸ may be linked together with theatoms to which they are attached to form N--C₄ -C₇ -alkylene orN--(CH₂)_(q) --G--(CH₂)_(q) --, wherein q and G are as defined above;

(15) R⁹ --S--C₁ -C₆ -alkyl-, wherein: R⁹ is:

(i) C₁ -C₆ -alkyl,

(ii) C₂ -C₆ -alkenyl,

(iii) aryl-C₁ -C₆ -alkyl-,

(iv) substituted aryl-C₁ -C₆ -alkyl-, or

(v) R⁷ --E--C(O)--, wherein R⁷ and E are as defined above;

(16) R¹⁰ --S(O)_(n) --C₁ -C₆ -alkyl-, wherein:

n is 1 or 2, and

R¹⁰ is C₁ -C₆ -alkyl-, aryl-C₁ -C₆ -alkyl-, or substituted aryl-C₁ -C₆-alkyl-;

(17) R¹¹ --NH--C₁ -C₆ -alkyl-, wherein: R¹¹ is:

(i) hydrogen,

(ii) N-protecting group, as defined below, or

(iii) R⁷ --J--CO--, wherein R⁷ is as defined above, and J is:

(a) absent,

(b) ethylene,

(c) substituted ethylene,

(d) O,

(e) O--CH₂,

(f) S,

(f) S--CH₂,

(h) NH, or

(i) N(C₁ -C₃ -alkyl); and

(18) when R² is hydrogen and R³ and R⁴ are linked to form ##STR3##wherein Q, R¹⁷ and r are as defined below, --C₁ -C₆-alkyl-CO--N(R¹²)(R¹³), wherein: R¹² is hydrogen or C₁ -C₃ -alkyl, andR¹³ is C₁ -C₃ -alkyl, aryl, or aryl-C₁ -C₃ -alkyl, or R¹² and R¹³ arelinked together with the N to which they are attached to form C₄ -C₇-alkylene or --(CH₂)_(q) --G--(CH₂)_(q) --, wherein q and G are asdefined above; or

(19) D is linked together with R² and atoms to which they are attachedto form C₄ -C₇ -alkylene or --(CH₂)_(q) --G--(CH₂)_(q) --, wherein q andG are as defined above; or

(20) D is linked together with R³ and atoms to which they are attachedto form --CO--N--C₃ -C₆ -alkylene or --CO--N--(CH₂)_(q) --G--(CH₂)_(q)--, wherein q and G are as defined above;

R³ is hydrogen or if R² or D is hydrogen, then additionally:

(1) C₁ -C₆ -alkyl,

(2) C₁ -C₃ -alkyl-O--C₁ -C₃ -alkyl,

(3) C₂ -C₆ -alkenyl,

(4) aryl-C₁ -C₆ -alkyl-,

(5) C₃ -C₇ -cycloalkyl, or

(6) --C₁ -C₆ -alkylene-CO₂ -R¹⁴, wherein R¹⁴ is C₁ -C₆ -alkyl or C₃ -C₇-cycloalkyl;

or,

R³ and D may be linked together to form --CO--N--C₃ -C₅ -alkylene or--CO--N--(CH₂)_(q) --G--(CH₂)_(q) --, wherein q and G are as definedabove;

R⁴ is selected from the group consisting of:

(1) C₁ -C₃ -alkyl,

(2) C₁ -C₃ -alkyl-O--C₁ -C₃ -alkyl,

(3) C₂ -C₄ -alkenyl,

(4) aryl,

(5) aryl-C₁ -C₆ -alkyl-,

(6) C₃ -C₇ -cycloalkyl,

(7) cyano-C₁ -C₆ -alkyl, or

(8) --C₁ -C₃ -alkylene-CO₂ -R¹⁴, wherein R¹⁴ is C₁ -C₆ -alkyl, C₃ -C₇-cycloalkyl, aryl, or aryl-C₁ -C₆ -alkylene;

or,

if R² is hydrogen, then R³ and R⁴ may be additionally linked to form:##STR4## wherein: r is independently at each occurrence 1 or 2, Q is CH₂or 0, and

R¹⁷ represents one or two substituents independently selected from thegroup consisting of:

(1) hydrogen,

(2) C₁ -C₆ -alkyl,

(3) aryl, and

(4) --C(O)--R¹⁸,

wherein

R¹⁸ is:

(i) aryl,

(ii) substituted aryl,

(iii) heteroaryl,

(iv) aryl-C₁ -C₃ -alkyl-,

(v) substituted aryl-C₁ -C₃ -alkyl, or

(vi) N--R¹⁹ R²⁰, wherein:

R¹⁹ is H or C₁ -C₃ alkyl, and

R²⁰ is aryl, aryl-C₁ -C₆ -alkyl-, or

heteroaryl-C₁ -C₆ alkyl-.

Alkyl refers to straight- or branched-chain alkyl radicals containingthe indicated number of carbon atoms, for example, C₁ -C₆ -alkyl, whichcontains from 1-to-6 carbon atoms including, but not limited to, methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl,2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl,2,2-dimethylbutyl, and the like.

Mono-substituted-C₁ -C₆ -alkyl refers to a C₁ -C₆ -alkyl chainsubstituted by one of: methyl, ethyl, oxo, hydroxyl, O-(hydroxylprotecting group), halo, halo-C₁ -C₆ -alkyl, cyano, CO₂ H, and CO₂ -C₁-C₆ -alkyl, or CO₂ -C₁ -C₆ -alkyl-aryl.

Substituted ethylene refers to an ethylene group substituted with one ortwo substituents independently selected from C₁ -C₆ alkyl, halo, halo-C₁-C₆ -alkyl and cyano.

C₂ -C₆ -alkenyl refers to a straight- or branched-chain of 2-to- 6carbon atoms containing one carbon-carbon double bond including, but notlimited to, vinyl, allyl, butenyl and the like.

C₁ -C₂ -alkylene refers to a straight- or branched-chain spacer groupcontaining one or two carbon atoms including --CH₂ --, --CH(CH₃)--, and--CH₂ -CH₂ --.

C₁ -C₃ -alkylene refers to a straight- or branched-chain spacer groupcontaining 1-to-3 carbon atoms including, but not limited to,--(CH₂)--,--(CH₂)₂ --, --CH(CH₃)CH₂ --, and the like.

C₄ -C₆ -alkylene refers to a straight- or branched-chain spacer groupcontaining 4-to-6 carbon atoms including, but not limited to, --(CH₂)₄--, --(CH₂)₂ --CH(CH₃)--, --CH(CH₂ CH₃)CH₂ --, and the like.

Aryl refers to a monocyclic or bicyclic aromatic carbocyclic ring systemof 6-11 carbon atoms including, but not limited to, phenyl, naphthyl,indanyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, isoindenyl and the like.

Substituted aryl refers to an aryl group substituted with one or twosubstituents, independently selected from C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy,C₁ -C₆ -thioalkoxy, aryl-C(O)--O, aryl-C₁ -C₆ -alkyl-C(O)--O--,--C(O)O--C₁ -C₆ -alkyl, --OSO₃ H, cyano, halo, haloalkyl, nitro,hydroxy, --C(O)NH₂, --C(O)--NH(C₁ -C₆ -alkyl), --C(O)N(C₁ -C₆-alkyl).sub. 2, --C(O)NH(C₃ -C₆ -alkenyl), --NH(C₁ -C₆ -alkyl), and--N(C₁ -C₆ -alkyl)₂.

C₃ -C₇ -cycloalkyl refers to an alicyclic ring having 3-to-7 carbonatoms including, but not limited to, cyclopropyl, cyclopentyl,cyclohexyl and the like.

C₃ -C₇ -cycloalkyl-C₁ -C₆ -alkyl- refers to a C₃ -C₇ -cycloalkyl groupappended to a C₁ -C₆ -alkyl radical including, but not limited to,cyclopropylmethyl, cyclohexylethyl, and the like.

Halo refers to F, Cl, Br, or I.

Halo-C₁ -C₃ alkyl refers to a C₁ -C₃ alkyl radical in which one or morehydrogen atoms have been substituted by halo groups, and including butnot limited to fluoromethyl, trifluoromethyl, chloroethyl,2,2-difluoroethyl, 2,3-dibromopropyl, and the like.

Heteroaryl refers to thienyl, pyridyl, pyrazinyl, benzofuranyl, indolyl,oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl,isoindazolyl, benzothiofuranyl, benzopyranyl, quinolyl, isoquinolyl,napthiridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, quinoxadinyl, ortetrahydrocarbolinyl.

Substituted heteroaryl refers to a heteroaryl group substituted with oneor two substituents independently selected from methyl, halo,trifluoromethyl, hydroxy, oxo, cyano, phenyl, and protected hydroxyl.

Het refers to thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, piperidyl,piperazinyl, benzofuranyl, indazolyl, 7-azaindolyl, isoindazolyl,benzopyranyl, quinolyl, isoquinolyl, or carbolinyl.

Substituted Het refers to a Het heterocycle, as defined above,substituted with one or two substituents independently selected from C₁-C₆ -alkyl, haloalkyl, oxo, hydroxy, protected hydroxyl, alkoxy,thioalkoxy, amino, --C(O)NH₂, --C(O)NH(C₁ -C₆ -alkyl), --C(O)N(C₁ -C₆-alkyl)₂, --NH(C₁ -C₆ -alkyl), --N(C₁ -C₆ -alkyl)₂, N-protected amino.protected hydroxyl, --CO₂ H, aryl-S(O)₂ -, substituted aryl-S(O)₂ -,cyano, nitro, and phenyl.

N-protecting group refers to those groups intended to protect theN-terminus of an amino acid or peptide or to protect an amino groupagainst undesirable reactions during synthetic procedures or to preventthe attack of exopeptidases on the compounds or to increase thesolubility of the compounds and includes, but is not limited to,sulfonyl, acyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc),carbobenzyloxy (Cbz), benzoyl or an a-aminoacyl residue, which mayitself be N-protected similarly.

Hydroxy-protecting group or O-protecting group refers to a substituentwhich protects hydroxyl groups against undesirable reactions duringsynthetic procedures and includes, but is not limited to, substitutedmethyl ethers, for example methoxymethyl, benzyloxy-methyl,2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl, andtriphenylmethyl; terahydropyranyl ethers; substituted ethyl ethers, forexample, 2,2,2-trichloroethyl and t-butyl; silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; cyclicacetals and ketals, for example, methylene acetal, acetonide andbenzylidene acetal; cyclic ortho esters, for example, methoxymethylene;cyclic carbonates; and cyclic boronates.

Exemplary compounds of the present invention include:

N-(3'-Quinolylcarbonyl)-R-valine-di-n-pentylamide;

N-(2'-Indolylcarbonyl)-R-valine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-valine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-valine-di-n-pentylamide;

N-(2'-Naphthoyl)-R-valine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-norleucine-di-n-pentylamide;

N-(2'-Indolylcarbonyl)-R-norleucine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-norleucine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-(O-benzyl)serine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-(O-benzyl)serine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-benzyl)threonine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-(2R,3S)-(O-benzyl)threonine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-(2R,3S)-threonine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-(2R,3S)-threonine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-acetyl)threonine-di-n-pentylamide;

N-(3 '-Quinolylcarbonyl)-(2R,3S)-(O-methyl)threonine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-3-(2'-thienyl)-R-alanine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-3-(2'-thienyl)-R-alanine-di-n-pentylamide;

N-(2'-Indolylcarbonyl)-R-histidine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-histidine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-histidine-di-n-pentylamide;

N^(a)-(3'-Quinolylcarbonyl)-Nε-(benzyloxycarbonyl)-R-lysine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-phenylalanine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-phenylalanine-di-n-pentylamide;

N^(a) -(3'-Quinolylcarbonyl)-N.sup.ε-(2'-chlorobenzyloxycarbonyl)-R-lysine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-(4'-hydroxyphenyl)glycine-di-n-pentylamide;

N.sup.α -(3'-Quinolylcarbonyl)-N.sup.ε-(acetyl)-R-lysine-di-n-pentylamide;

N-(2'-Indolylcarbonyl)-R-tyrosine-di-n-pentylamide;

N-(3',4'-Dichlorobenzoyl)-R-tyrosine-di-n-pentylamide;

N-(2'-Naphthoyl)-R-tyrosine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-tyrosine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-tyrosine-di-n-pentylamide;

Methyl N-(3'-quinolylcarbonyl)-R-tyrosyl-S-phenylglycinate;

Methyl N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-tyrosyl-S-phenylglycinate;

N-(2'-Indolylcarbonyl)-R-homoserine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-homoserine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-homoserine-di-n-pentylamide;

N-(2'-Indolylcarbonyl)-R-methionine-di-n-pentylamide;

N-(2'-Indolylcarbonyl)-R-methioninesulfoxide-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-methionine-di-n-pentylamide;

N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-methionine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-ioninesulfoxide-di-n-pentylamide;

N.sup.α -(3'-Quinolylcarbonyl)-N.sup.ε-phenylthiolcarbonyl-R-lysine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-tyrosine-di-n-pentylamide hydrochloride;

N-(3'-Quinolylcarbonyl)-R-histidine-di-n-pentylamide dihydrochloride;

N-(2'-Indolylcarbonyl)-glycine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-glycine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide;

N-(5'-Fluoroindolylcarbonyl)-R-phenylglycine-di-n-pentylamide;

N-(5'-Chloroindolylcarbonyl)-R-phenylglycine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-glycine-di-n-pentylamide;

N-(2'-Naphthoyl)-glycine-di-n-pentylamide;

N-(3'- Methylphenylaminocarbonyl)-glycine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-(4'-hydroxyphenyl)-glycine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-(2R,3S)-(O-benzyl)-threonine-di-n-pentylamide;

MethylN-(2'-Indolylcarbonyl)-R-methionine-S-(p-hydroxy)-phenylglycinate;

MethylN-(3'-Quinolylcarbonyl)-R-methionine-S-(p-hydroxy)-phenylglycinate;

MethylN-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-methionine-S-(p-hydroxy)-phenylglycinate;

N-(3'-Quinolylcarbonyl)-R-serine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-serine-di-n-pentylamide;

N-(8'-Hydroxy-2-quinolylcarbonyl)-glycine-di-n-pentylamide;

N-Methyl-N-(3'-quinolylcarbonyl)-glycine-di-n-pentylamide;

N-(3'-Iodo-2'-indolylcarbonyl)-glycine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-alanine-di-n-pentylamide;

N-(2'-Indolylcarbonyl)-R-alanine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-alanine-di-n-pentylamide;

N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-aspartyl-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(γ-pyrrolidin-1-yl)-R-glutamyl-4'-benzoylpiperidide;

N-(m-Methoxyphenylaminocarbonyl)-(γ-pyrrolidin-1-yl)-R-glutamyl-4'-benzoylpiperidide;

N-(Phenylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide;

N-(m-Methoxyphenylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide;

N-(m-chlorophenylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide;

N-(m-acetylphenylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(S-benzyl)-S-cysteine-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(S-benzyl-S,S-dioxo)-S-cysteine-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(S-benzyl-S-oxo)-S-cysteine-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-(4-fluorobenzoyl)piperidide;

N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-piperidine-4'-carboxanilide;

N-(m-Toluylaminocarbonyl)-(γ-pyrrolidin-1-yl)-R-glutamylpiperidine-4'-carboxanilide;

N-(m-Toluylaminocarbonyl)-(β-O-pyrrolidinecarbamoyl)-R-serine-piperidine-4'-carboxanilide;

N-(m-Toluylaminocarbonyl)-(β-O-benzylcarbamoyl)-R-serine-piperidine-4'-carboxanilide;

N-(m-Toluylaminocarbonyl)-(β-O-(N,N-dimethylaminocarbamoyl))-R-serine-piperidine-4'-carboxanilide;

N-(m-Toluylaminocarbonyl)-(β-O-(N,N-diethylaminocarbamoyl))-R-serine-piperidine-4'-carboxanilide;

N-(m-Toluylaminocarbonyl)-(β-O-pyrrolidinecarbamoyl)-R-serine-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(β-O-morpholinecarbamoyl)-R-serine-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(β-O-anilinecarbamoyl)-R-serine-4'-benzoylpiperidide;

(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-piperidine-4'-m-bromocarboxanilide;or

N-(3'-Quinolylcarbonyl)-2-allyl-R,S-phenylalanine-n-pentylamide.

Exemplary of the preferred compounds of the invention are:

N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-methyl)threonine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-(2R,3S)-threonine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-histidine-di-n-pentylamide dihydrochloride;

N-(3'-Quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-serine-di-n-pentylamide;

Methyl N-(3'-quinolylcarbonyl)-R-tyrosyl-S-phenylglycinate;

N-(3'-Quinolylcarbonyl)-R-(4'-hydroxyphenyl)glycine-di-n-pentylamide;

N-(2'-Indolylcarbonyl)-R-histidine-di-n-pentylamide;

N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-valine-di-n-pentylamide;

N-(2'-Quinolylcarbonyl)-R-valine-di-n-pentylamide;

N-(3'-Quinolylcarbonyl)-R-valine-di-n-pentylamide;

N-(m-Toluylaminocarbonyl)-(γ-pyrrolidin-1-yl)-R-glutamyl-4'-benzoylpiperidide;

N-(m-Methoxyphenylaminocarbonyl)-(γ-pyrrolidin-1-yl)-R-glutamyl-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(S-benzyl-S-oxo)-(S)-cysteine-4'-benzoylpiperidide;

N-(m-Toluylaminocarbonyl)-(β-O-pyrrolidinecarbamoyl)-R-serine-piperidine-4'-carboxanilide;or

N-(m-Toluylaminocarbonyl)-(β-O-pyrrolidinecarbamoyl)-R-serine-4'-benzoylpiperidide

The compounds of the invention may be made as shown in the followingscheme(s). The compounds of the invention having one asymmetric centercan exist as separate enantiomers or as mixtures of enantiomers. Thecompounds of the invention which contain two or more asymmetric carbonatoms can exist as pure diastereomers, mixtures of distereomers,diastereomeric racemates or mixtures of diastereomeric racemates. Thepresent invention includes within its scope all of the isomeric forms.

A number of synthetic pathways exist for the production of α-amino acidsand their derivatives. The invention is not limited to those methodsdiscussed here for the synthesis of α-amino acids but is meant toinclude those variations and methods encompassed by the prior art asdiscussed in the chemical literature in its entirety. α-Amino acids(refer to Scheme 1) can be produced directly by the displacement ofα-halogenated esters (1, X is halo) and the like or other α-situatedleaving groups by ammonia and or other substituted amines (R₁ ishydrogen, loweralkyl, carboxyester-substituted alkyl) and/or theiranalogs (e.g., carbamates, hydrazines, azides) (e.g., Marvel, Org.Synth, 20, 81, 1940; 106, 1940; 21, 60, 1941; 74, 1941; Birnbaum, J.Biol, Chem., 333, 1953). The antino group is then unmasked, for exampleby reduction, and the ester group (amide, etc.) is saponified to theacid in a standard fashion.

A second method involves the condensation of an α-ketoester (amide, etc)with an amine or amine equivalent (e.g., hydroxylamine, hydrazine,carbamate, etc.) and the subsequent reduction of this product (2) to theα-aminoester (amide, acid, etc. (e.g., Can, J. Chem., 29, 427, 1951; J.Org. Chem., 38, 822, 1973; J. Org. Chem., 6, 878, 1941)). Alternatively,an organometalic reagent can be added to the oxime 2 (imine, etc.) toprovide as final products either monosubstituted α-amino acids in thecase where D is hydrogen, or disubstituted amino acids in the case whereD is other than hydrogen (e.g., Tetrahedron Lett., 28(42), 4973, 1987).

A third method is the alkylation of a carbanion resulting from compound(3) with an electrophilic nitrogen source (e.g.diethylazodicarboxylate). The intermediate product can subsequently beunmasked to provide the desired α-amino acid. A similar method involvesalkylation of the carbanion derived from compound (4) with anappropriate alkylating agent. This method also allows for thepossibility of disubstitution of the α center.

A fifth route involves the Strecker reaction and its modifications.Reaction of cyanide and ammonium on aldehydes and ketones (5) providesthe amino acid.

A last method involves the direct reduction of unsaturated heterocycliccarboxylic acids (6) to directly provide the cyclic amino acids (7),(wherein D and R¹ are encompassed in a ring).

With suitably available α-amino acids (8) (Scheme 2) the amino group isprotected with an N protecting group (most frequently Boc or Cbz) and,if the carboxylic acid has not been unmasked, it is saponified with baseto provide the parent carboxylic acid (9). The N-protected intermediateis then coupled with the amine HNR³ R⁴ using any of a number of standardcoupling techniques (carbodiimide, BOPCl, chloroformates,oxalylchloride, etc.). Preferred secondary amines are of the type whereR³ and R⁴ are alkyl, arylalkyl, aryl, are connecting such as to form acyclic secondary amine when taken together with the adjacent nitrogen,or represent another amino acid. The resulting product (10) is thenN-deprotected using HCl or trifluoroacetic acid (TFA) to remove a Bocgroup and hydrogenolysis or HBr to remove a Cbz group. The resultantamine (11) is then coupled with aromatic carboxylic acids, aromatic acidhalides, heteroaromatic carboxylic acids, aromatic isocyanates, and thelike using standard coupling techniques to provide the desired products(12), (13), and (14). Preferred acyl coupling partners groups include:quinoline carboxylic acids, indole carboxylic acids, substituted benzoicacids and benzoyl chlorides, arylisocyanates and naphthoic acids,benzothiofuranyl carboxylic acids and the like. ##STR5##

Intermediates for the preparation of the compounds of formula I includecompounds of the formula: ##STR6## wherein D, R¹, R², R³, and R⁴ are asdefined above, and P¹ is hydrogen or an N-protecting group.

Other intermediates for the preparation of compounds of the formula Iinclude compounds of the formula: ##STR7## wherein A and B are asdefined above, Z' is an activating group; or B--C(O)--Z' taken togetherrepresent --N═C═O, or --CH₂ --N═C═O.

Activating groups are those functional groups which activate acarboxylic acid group toward coupling with an amine to form an amide.Activating groups Z' include, but are not limited to, --OH, --SH,alkoxy, thioalkoxy, halogen, formic and acetic acid derived anhydrides,anhydrides derived from alkoxycarbonyl halides such asisobutyloxycarbonylchloride and the like, N-hydroxysuccinimide derivedesters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazolederived esters, N-hydroxy-5-norbornene-2,3-dicarboxamide derived esters,4-nitrophenol derived esters, 2,4,5-trichlorophenol derived esters andthe like.

The following examples will serve to further illustrate preparation ofthe novel compounds of this invention.

EXAMPLE 1 N-(3'-Quinolylcarbonyl)-R-valine-di-n-pentylamide Step 1a.N-(t-Butyloxycarbonyl)-R-valine-di-n-pentylamide

N-t-Butyloxycarbonyl-R-valine (2.5 g, 11.5 mmol) was stirred at 0° C. in30 mL of methylene chloride (CH₂ Cl₂) withbis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl, 3.5 g, 13.8 mmol)and 1.5 mL (11.5 mmol) of triethylamine (TEA). To this reaction mixturewas added di-n-pentylamine (11.6 mL, 58 mmol). The mixture was stirredovernight and allowed to warm to room temperature. An additionalequivalent of BOPCl was added after 18 hrs and the reaction mixture wasstirred an additional day at ambient temperature. The solvents wereevaporated in vacuo and the residue taken up in ethylacetate (EtOAc) andwashed with water, 1N hydrochloric acid (HCl) solution, saturated sodiumbicarbonate solution (NaHCO₃), water. The organic solution was driedover magnesium sulfate (MgSO₄). After filtration and concentration ofthe filtrate in vacuo, the residue was chromatographed usingEtOAc-hexane as the solvent system in the ratio (1:4). The product wasisolated as an oil 79% yield (3.25 g). [α]_(D) =+21.2° (c=1.5, MeOH).MS(CI) m/e 357(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 0.85-1.0(m,12H), 1.32(m,8H), 1.4-1.5(m,4H), 1.5(s,9H), 1.84(m,1H), 3.05(m,1H), 3.2(m,1H),3.35(m,1H), 3.55(m,1H), 4.42(m,1H), 5.25(d,J=7 Hz,1H).

Step 1b. R-Valine-di-n-pentylamide hydrochloride

The product of example 1a (0.2 g, 0.6 mmol) was dissolved in 4N HCl indioxane (10 mL) and stirred under inert atmosphere (N₂) for an hour.When the reaction was complete by tlc the solvents were evaporated invacuo and hexane and diethylether were added. The residue was trituratedwith these two solvents and the solvents again evaporated in vacuo. Thisprocedure was repeated several times until product was obtained as aglass in quantitative yield. MS(CI) m/e 293(m+H)⁺.

Step 1c. N-(3'-Quinolylcarbonyl)-R-valine-di-n-pentylamide

The hydrochloride of example 1b (150 mg, 0.5 mmol),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI, 100 mg), HOBt (135mg) and quinoline-3-carboxylic acid (88 mg) were stirred at 0° C. undernitrogen in 5 mL of anhydrous CH₂ Cl₂. To this mixture was added 120 μLof N-methylmorpholine (NMM) and the mixture was stirred overnight(warming to ambient temperature). The reaction mixture was poured intoEtOAc and water and the organic extract was washed successively withwater, 10% citric acid solution, and saturated aqueous NaHCO₃. Thesolution was dried over MgSO₄, filtered and concentrated. The residuewas chromatographed using ethylacetate (EtOAc) and hexane as the elutantmixture to provide 110 mg of an oil (54% yield) after removal of thevolatiles. [α]_(D) =-14.8° (c=0.5, MeOH). MS(CI) m/e 412(m+H)⁺. ¹ HNMR(CDCl₃,300 MHz) δ 0.92(m,6H), 1.05(m,6H), 1.35(m,8H), 1.5-1.7(m,4H),2.15(m,1H), 3.05(m,1H), 3.3-3.4(m,1H), 3.5(m,1H), 3.65(m,1H),5.08(dd,J=3,9 Hz,1H), 7.25(d,J=9 Hz,1H), 7.62(t,J=7 Hz, 1H), 7.8(t,J=7Hz,1H), 7.91(d,J=10 Hz, 1H), 8.16(d,J=10 Hz,1H), 8.6(d, J=3 Hz,1H),9.35(d,J=3 Hz,1H). Analysis calculated for C₂₅ H₃₇ N₃ O₂ : C 72.95, H9.06, N 10.21; found: C 72.61, H 9.21, N 9.97.

EXAMPLE 2 N-(2'-Indolylcarbonyl)-R-valine-di-n-pentylamide

The hydrochloride of example 1b (130 mg, 0.45 mmol), EDCI (90 mg), HOBt(120 mg) and indole-2-carboxylic acid (75 mg) were stirred at 0° C.under nitrogen in 5 mL of anhydrous CH₂ Cl₂. To this mixture was added100 μL of NMM and the mixture was stirred overnight (warming to ambienttemperature). The reaction mixture was poured into EtOAc and water andthe organic extract was washed successively with water, 10% citric acidsolution, and saturated aqueous NaHCO₃. The solution was dried overMgSO₄, filtered and concentrated. The residue was chromatographed usingEtOAc and hexane as the elutant mixture to provide 36 mg of product (75%yield) after evaporation of the volatiles. mp=132°-4° C. [α]_(D) =-9.2°(c=0.5, MeOH). MS(CI) m/e 400(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 0.9(t,J=7Hz,6H), 1.0(m,6H), 1.2-1.4(m,8H), 1.5-1.6(m,4H), 2.12(m, 1H),3.05(m,1H), 3.3(m,1H), 3.42(m,1H), 3.63(m,1H), 5.0(q,J=3,6 Hz,1H),7.0(m,1H), 7.1(d,J=9 Hz, 1H), 7.25(t,J=7.5 Hz,1H), 7.3(t,J=7.5 Hz,1H),7.41(d,J=7 Hz,1H), 7.65 (d,J=7 Hz,1H), 9.3(bs,1H). C,H,N analysiscalculated for C₂₄ H₃₇ N₃ O₂ : C 72.14, H 9.34, N 10.52; found: C 72.52,H 9.25, N 10.49.

EXAMPLE 3 N-(2'-Quinolylcarbonyl)-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1cutilizing 0.2 g of the hydrochloride salt of example 1b,quinoline-2-carboxylic acid (0.12 g), EDCI (0.15 g), HOBt (0.1 g), andNMM (6.18 mL). The product was isolated in 80% yield (0.225 g).mp=78°-79° C. [α]_(D) =-13.1° (c=1.1, MeOH). MS(CI) m/e 412(M+H)⁺. ¹ HNMR(CDCl₃,300 MHz) δ 0.9(m,6H), 1.05(m,6H), 1.2-1.4(m,8H), 1.55(m,4H),2.22(m,1H), 3.08(m,1H), 3.4(m,2H), 3.64(m,1H), 5.0(dd,J=3,7 Hz,1H),7.62(t,J=7 Hz,1H), 7.78(t,J=7 Hz,1H), 7.85(d,J=9 Hz,1H), 8.15(d,J=9Hz,1H), 8.35(m,2H), 8.85(d,J=10 Hz,1H). C,H,N analysis calculated forC₂₅ H₃₇ N₃ O₂, H₂ O: C72.17, H 8.96, N 10.10; found: C 72.36, H 8.93, N10.03.

EXAMPLE 4 N-(2'-Benzothiofuranylcarbonyl)-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1cutilizing 0.3 g of the hydrochloride salt of example 1b,benzothiofuran-2-carboxylic acid (0.205 g), EDCI (0.22 g) HOBt (0.28 g),and NMM (0.22 mL). The oily product was isolated in 58% yield, 0.28 g[α]_(D) =-5.85° (c=2.0, MeOH). MS(CI) m/e 417(m+H)⁺, 158. ¹ HNMR(CDCl₃,300 MHz) δ 0.9-1.1(m,12H), 1.2-1.3(m,8H), 1.5-1.6(m,4H),2.15(m,1H), 3.05(m,1H), 3.3(m,1H), 3.42(m,1H), 3.65(m,1H), 5.0(q,J=3,6Hz,1H), 7.00(d,J=9 Hz,1H), 7.41(m,2H), 7.80(s,1H), 7.86(m,2H). C,H,Nanalysis calculated for C₂₄ H₃₆ N₂ O₂ S, 0.25 H₂ O: C 68.45, H 8.74, N6.65; found: C 68.73, H 8.48, N 6.71.

EXAMPLE 5N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-valine-di-n-pentylamide

The hydrochloride salt of example 1b (0.95 g, 3.22 mmol) was stirred in25 mL of CH₂ Cl₂ with NMM (0.7 mL) under nitrogen at 0° C. EDCI (0.7 g)and HOBt (0.11 g) were added followed by the addition of4,8-dihydroxyquinoline-2-carboxylic acid (0.66 g, 3.22 mmol). Thereaction mixture was stirred overnight (warming to ambient temperature).The solvents were evaporated in vacuo and the residue taken up in EtOAcand washed successively with water, 0.1N solution of HCl, water andbrine. The organic solution was dried over MgSO₄ and then filtered.Solvents were evaporated in vacuo and the crude product subjected toflash chromatography using EtOAc, hexane and methanol (MeOH) as theelutant mixture. The product was crystallized from MeOH-water to provide0.82 g (56%). mp=233°-235° C. [α]_(D) =-15.6° (c=0.5, MeOH). MS(CI) m/e444(m+H)⁺. ¹ H NMR(DMSO_(d6) ,300 MHz) δ 0.84(m,6H), 0.92(m,6H),1.1-1.35(m,8H), 1.4-1.6(m,4H), 2.33(m,1H), 3.1-3.45(m,2H), 3.55(m,2H),4.67(m,1H), 7.1(d,J=9 Hz,1H), 7.42(t,J=7 Hz,1H), 7.55(m,2H), 9.62(d,J=9Hz,1H), 10.3(s,1H), 11.75(s,1H). C,H,N calculated for C₂₅ H37N₃ O₄ : C67.69 H 8.41, N 9.47; found: C 67.47 H 8.45, N 9.39.

EXAMPLE 6 N-(2'-Benzofuranylcarbonyl)-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 5utilizing 0.3 g of the hydrochloride salt of example 1b,benzofuran-2-carboxylic acid (0.19 g), EDCI (0.22 g), HOBt (0.28 g), andNMM (0.22 mL). Product was isolated in 56% yield (0.225 g). [α]_(D)=-29.2° (c=1.1, MeOH). MS(CI) m/e 401(m+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ0.9-1.0(m,6H), 1.05(m,6H), 1.25-1.4(m,8H), 1.5-1.68(m,4H), 2.15(m,1H),3.1(m,1H), 3.28-3.5(m,2H), 3.62(m,1H), 5.0(dd,J=3,6 Hz,1H), 7.28(t,J=5Hz,1H), 7.4(t,J=8 Hz,2H), 7.45(s,1H), 7.52(d,J=9 Hz,1H), 7.65(d,J=9Hz,1H). C,H,N analysis calculated for C₂₄ H₃₆ N₂ O_(3:) C 71.96, H 9.06,N 6.99; found: C72.09, H 9.08, N 6.99.

EXAMPLE 7N-[4'-Hydroxy-2'-phenyl-3'-quinolylcarbonyl]-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 5utilizing 0.2 g of the hydrochloride salt of example 1b,4-hydroxy-2-phenyl-quinoline-3-carboxylic acid (0.18 g), EDCI (0.16 g),HOBt (0.19 g), and NMM (0.16 mL). Product was isolated in 64% yield(0.22 g). mp=154°-155° C. [α]_(D) =-30.0° (c=0.4, MeOH). MS(CI) m/e504(m+H)⁺. ¹ H NMR(DMSO_(d6),300 MHz) δ 0.82(m, 14H), 1.2(m,8H),1.38(m,4H), 1.94(m,1H), 3.02(m,2H), 3.2(m,1H), 3.4(m,1H), 4.55(m,1H),7.43(m,SH), 7.7(m,2H), 8.2 (d,J=7 Hz,1H), 12.02(s,1H). C,H,N analysiscalculated for C₃₁ H₄₁ N₃ O₃ : C 73.93, H 8.21, N 8.34; found: C73.73, H8.18, N 8.34.

EXAMPLE 8N-(7'-Chloro-4'-hydroxy-3'-quinolylcarbonyl)-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 5utilizing 5.0 g of the hydrochloride salt of example 1b,4-hydroxy-7-chloro-quinoline-3-carboxylic acid (3.8 g), EDCI (3.5 g),HOBt (4.6 g), and NMM (3.8 mL) and 10 mL DMF. Product was isolated in54% yield, 4.25 g. mp=205°-206° C. [α]D =-93.8° (c=0.5, MeOH). MS(CI)m/e 463(m+H)⁺. ¹ H NMR(DMSO_(d6), 300 MHz) δ 0.95(m,6H), 1.15(d,J=8Hz,3H), 1.26(d,J=8 Hz,3H), 1.38 (m,8H), 1.65(m,2H), 1.8(m,1H),2.0(m,1H), 2.23(m,1H), 3.15(m,1H), 3.35(m,1H), 3.48(m,1H), 3.72(m,1H),4.6(t,J=6 Hz,1H), 7.2(dd, J=3,9 Hz, 1H), 7.6(d,J=9 Hz,1H) 7.68(d,J=2Hz,1H), 8.26(d, J=7 Hz,1H), 10.25(d,J=6 Hz,1H), 12.25(d,J=9 Hz,1H).C,H,N analysis calculated for C₂₅ H₃₆ C₁ N₃ O₃ : C 64.98, H 7.85, N9.09, Cl 7.67; found: C 65.16, H 8.04, N 8.94, Cl 7.91.

EXAMPLE 9 N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 5utilizing 0.2 g of the hydrochloride salt of example 1b,4-hydroxyquinoline-2-carboxylic acid (0.13 g), EDCI (0.14 g), HOBt (0.19g), and NMM (0.15 mL). Product was isolated in 71% yield (0.207 g).mp=70°-71° C. [α]_(D) =-13.3° (c=0.6, MeOH). MS(CI) m/e 428(m+H)⁺. ¹ HNMR(DMSO_(d6),300 MHz) δ 0.85-1.1 (m,12H), 1.2-1.4(m,SH), 1.5-1.7(m,4H),2.15(m,1H), 3.02(m,1H), 3.25(m,1H), 3.45(m,1H), 3.64(m,1H),4.95(dd,J=3,6 Hz, 1H), 6.7(bs, 1H), 7.35-7.5(m,2H), 7.65(t,J=7 Hz,2H),8.35(d,J=8 Hz, 1H), 10.4(bs, 1H). C,H,N analysis calculated for C₂₅ H₃₇N₃ O₃ : C 70.22, H 8.72, N 9.83; found: C 69.91, H 8.71, N 9.68.

EXAMPLE 10N-[Z-2'-Fluoro-3'-phenylprop-2'-enoyl]-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1cutilizing 0.27 g of the hydrochloride salt of example 1b,α-fluorocinnamic acid (0.16 g), EDCI (0.19 g), HOBt (0.25 g), and NMM(0.21 mL). The oily product was isolated in an 68% yield, 0.25 g [α]_(D)=+7.1° (c=1.1, MeOH). MS(CI) m/e 405(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ0.82-1.0(m,12H), 1.2-1.5(m,8H), 1.5-1.7(m,4H), 2.1(m,1H), 3.05(m,1H),3.25(m,1H), 3.4(m,1H), 3.6 (m1H), 4.85(m,1H), 7.05(d,J=42 Hz,1H),7.1(d,J=10 Hz,1H), 7.3-7.45(m,3H), 7.62(d,J=9 Hz,2H). C,H,N analysiscalculated for C₂₄ H₃₇ FO₂ N₂ : C 71.25, H 9.22, N 6.93; found: 70.99, H9.14, N 6.95.

EXAMPLE 11 N-(2'-Naphthoyl)-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1cutilizing 0.2 g of the hydrochloride salt of example 1b, 2-naphthoicacid (0.12 g), EDCI (0.13 g), HOBt (0.18 g), and NMM (0.16 mL). Theproduct was isolated as an oil in 72% yield, 0.2 g. [α]_(D) =-13.0°(c=1.0, MeOH). MS(CI) m/e 411(m+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ0.8-0.9(m,6H), 1.1(m,6H), 1.2-1.4(m,8H), 1.55-1.67(m,4H), 2.13(m,1H),3.0-3.1(m,1H), 3.25-3.3(m,1H), 3.5 (m, 1H), 3.65(m,1H), 5.08(dd,J=3,6Hz,1H), 7.11(d,J=9 Hz,1H), 7.52 (m, 2H), 7.9(m,4H), 8.33(s,1H). C,H,Nanalysis calculated for C₂₆ H₃₈ N₂ O₂ : C 76.05, H 9.33, N 6.82; found:C 76.20, H 9.32, N 6.98.

EXAMPLE 12 N-[3'-(3"-Pyridyl)prop-2'-enoyl]-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1cutilizing 0.3 g of the hydrochloride salt of example 1b,3-(3'pyridyl)acrylic acid (0.17 g), EDCI (0.22 g), HOBt (0.28 g), andNMM (0.22 mL). An oil was isolated in 76% yield, 0.3 g. [α]_(D) =+10.0°(c=0.85, MeOH). MS(CI) m/e 388(m+H)⁺. ¹ H NMR (CDCl₃,300 MHz)0.8-1.05(m,12H), 1.2-1.4(m,8H), 1.45-1.72 (m,4H), 2.06(m,1H), 3.1(m,1H),3.2-3.5(m,2H), 3.5-3.65(m,1H), 4.92(dd,J=2,6 Hz,1H), 6.6(d,J=15 Hz,1H),7.28(d,J=9 Hz,1H), 7.3(m, 1H), 7.6(d,J=15Hz,1H), 7.8(d,J=9 Hz,1H),8.58(d,J=6 Hz,1H), 8.74(d, J=2 Hz,1H). C,H,N analysis calculated for C₂₃H₃₇ N₃ O₂, 0.75 H₂ O: C 68.88, H 9.68, N 10.48; found: C 68.74, H 9.31,N 10.21.

EXAMPLE 13N-(1',2',(3'S),4'-Tetrahydrocarbolinyl-3'-carbonyl)-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1cutilizing 250 mg of the hydrochloride salt of example 1b,N-L-1,2,3,4-tetrahydroharman-3-carboxylic acid (270 mg), EDCI (160 mg),HOBt (235 mg), and NMM (190 mL). The oily product was isolated in 38%yield (148 mg). [α]D=-5.5° (c=0.2, MeOH). MS(CI) m/e 455(m+H)⁺. ¹ HNMR(CDCl₃,300 MHz) δ 0.8-1.0(m,12H), 1.2-1.35(m,8H), 1.5(m,4H),1.6(m,1H), 2.05(m,1H), 2.55-2.82(m,1H), 3.1-3.4(m,4H), 3.55(m,2H),4.1(m,1H), 4.75(m, 1H), 7.0-7.15(m,2H), 7.25(d,J=9 Hz,1H), 7.45(d,J=9Hz,1H), 7.8(bs,1H), 7.85(bs,1H), 8.26(s,1H). C,H,N analysis calculatedfor C₂₇ H₄₂ N₄ O₂, 0.75 H2O: C 9.27, H 9.36, N 11.97; found: C 69.58, H9.16, N 11.91.

EXAMPLE 14 N-(1'-Hydroxy-2'-naphthoyl)-R-valine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1cutilizing 250 mg of the hydrochloride salt of example 1b,1-hydroxy-2-naphthoic acid (160 mg), EDCI (180 mg), HOBt (240 mg), andNMM (200 μL). Product was isolated in 85% yield (310 mg). mp=85°-86° C.[α]_(D) =+90.5° (c=0.6, MeOH). MS(CI) m/e 427(m+H)⁺. ¹ H NMR(CDCl₃,300MHz) δ 0.9(m,6H), 1.05(m, 6H), 1.25-1.4(m,gH), 1.5-1.7(m,4H),2.15(m,1H), 3.05(m, 1H), 3.25(m,1H), 3.5(m,1H), 3.65(m,1H),5.06(dd,J=3,9 Hz, 1H), 7.2(d, J=9 Hz,1H), 7.35(d,J=10 Hz,1H),7.45(d,J=10 Hz,1H), 7.5(dd,J= 3,6 Hz, 1H), 7.6(dd,J=3,6 Hz,1H),7.75(d,J=7 Hz,1H), 8.4(d,J=9 Hz,1H), 10.6 (bs,1H). C,H,N analysiscalculated for C₂₆ H₃₈ N₂ O₃ : C 73.20, H 8.98, N 6.57; found: C 73.24,H 9.02, N 6.55.

EXAMPLE 15 N-(3'-Quinolylcarbonyl)-R-norleucine-di-n-pentylamide Step15a. N-(t-Butyloxycarbonyl)-R-norleucine-di-n-pentylamide

N-(t-Butyloxycarbonyl)or-norleucine (1.2 g, 5.2 mmol) was stirred at 0°C. in 40 mL of CH₂ Cl₂ with BOPCl (1.5 g, 5.9 mmol), and TEA (0.7 mL,5.2 mmol). To this reaction mixture was added di-n-pentylamine (2.5 mL,10.5 mmol). The mixture was stirred overnight and allowed to warm toroom temperature. An additional equivalent of BOPCl was added after 18hrs and the reaction stirred an additional day at ambient temperature.The solvents were evaporated in vacuo and the residue taken up in EtOAcand washed with water, 1N HCl, saturated NaHCO₃ solution, water and thenthe organic solution was dried over MgSO₄. After filtration andconcentration of the filtrate in vacuo, the residue was chromatographedusing EtOAc-hexane as the solvent system in the ratio (1:4). The productwas isolated as an oil in 75% yield (1.45 g). MS(CI) m/e 371(m+H)⁺, ¹ HNMR(CDCl₃, 300 MHz) a 0.9-1.2(m,9 H), 1.24-1.35(m,12H), 1.5(s,9H),1.55-1.6 (m,4H), 1.88(m,2H), 3.1(m,1H), 3.32(m,1H), 3.42(m,1H),3.6(m,1H), 5.15(m,1H), 6.9(d,J=10 Hz,1H).

Step 15b. R-Norleucine-di-n-pentylamide hydrochloride

The product of example 15a (1.4 g, 3.8 mmol) was dissolved in 4N HCl indioxane (25 mL) and stirred at room temperature for an hour. When thereaction was complete by tlc the solvents were evaporated in vacuo andhexane and diethylether were added. The residue was triturated withthese solvents and the solid product was filtered away in quantitativeyield. [α]_(D) =-1.4° (c=0.6, MeOH). MS(CI) m/e 27 1(m+H)⁺. ¹ HNMR(DMSO_(d6), 300 MHz) δ 0.87(m,9H), 1.2-1.4(m,12H), 1.42-1.6(m,4H),1.7(m,2H), 3.0(m,1H), 3.1-3.3(m,2H), 3.53(m,1H), 4.14(bs,1H),8.25(bs,2H).

Step 15c. N-(3'-Quinolylcarbonyl)-R-norleucine-di-n-pentylamide

The hydrochloride of example 15b (240 mg, 0.87 mmol), EDCI (170 mg),HOBt (240 mg) and quinoline-3-carboxylic acid (150 mg) were stirred at0° C. under nitrogen in 20 mL anhydrous CH₂ Cl₂. To this mixture wasadded 200 μL of NMM and the mixture was stirred overnight (warming toambient temperature). The reaction mixture was poured into EtOAc andwater and the organic extract was washed successively with water, 10%citric acid solution, and saturated aqueous NaHCO₃. The solution wasdried over MgSO₄, filtered and concentrated. The residue was purified bychromatography using EtOAc and hexane as the elutant mixture to provide200 mg of the glassy product (54% yield) after evaporation of thevolatiles. [α]_(D) =-10.5° (c=1.0, MeOH). MS(CI) m/e 426(m+H)⁺. ¹ HNMR(CDCl₃, 300 MHz) δ 0.9(m,9H), 1.35(m,12H), 1.55(m, 2H),1.65-1.80(m,4H), 3.10(m,1H), 3.25-3.35(m,1H), 3.4(m,1H), 3.55-3.6(m,1H),5.15(m,1H), 7.4(d, J=9 Hz,1H), 7.6(dd,J=3,7 Hz,1H), 7.8(dd,J=3,7 Hz,1H),7.9(d,J=9 Hz,1H), 8.15(d,J=9 Hz,1H), 8.6(d,J=2 Hz,1H), 9.35(d,J=3 Hz,1H). C,H,N analysis calculated for C₂₆ H₃₉ N₃ O₂, 0.3 EtOAc: C 72.27, H9.23, N 9.27; found: C 72.26, H 9.01, N 9.54.

EXAMPLE 16 N-(2'-Indolylcarbonyl)-R-norleucine-di-n-pentylamide

The hydrochloride salt of example 15b (0.30 g, 1.0 mmol) was stirred in10 mL of CH₂ Cl₂ with NMM (0.2 mL, 2.0 mmol) under nitrogen at 0° C.EDCI (0.2 g, 1.1 mmol) and HOBt (0.27 g, 2.0 mmol) were added followedby the addition of indole-2-carboxylic acid (0.162 g, mmol). Thereaction mixture was stirred overnight (warming to ambient temperature).The solvents were evaporated in vacuo, and the residue taken up in EtOAcand washed successively with water, saturated NaHCO₃, a saturatedsolution of citric acid, water and brine. The organic solution was driedover MgSO₄ and then filtered. Solvents were evaporated in vacuo and thecrude product subjected to flash chromatography using EtOAc and hexaneas the elutant mixture. The product was crystallized from EtOAc andhexane to provide a glass 0.285 g (69%). [α]_(D) =-10.6° (c=0.8, MeOH).MS(CI) m/e 414(m+H)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ 0.9(m,9H), 1.2-1.4(m,10H), 1.5-1.7(m,6H), 1.86(m,2H), 3.15(m,1H), 3.3-3.4(m,2H),3.58(m,1H), 5.1(m,1H), 7.0(d,J=2 Hz, 1H), 7.15(dd,J=3,7 Hz,1H),7.3(m,2H), 7.4(d,J=9 Hz,1H), 7.67(d,J=9 Hz, 1H), 9.4(s,1H). C,H,Nanalysis calculated for C₂₅ H₃₉ N₃ O₂, 0.75 H₂ O: C 70.30, H 9.55, N9.84; found: C 70.38, H 9.20, N 9.85.

EXAMPLE 17 N-(3'-Quinolylcarbonyl-R-(O-benzyl)serine-di-n-pentylamideStep 17a. N-(t-Butyloxycarbonyl)-R-(O-benzyl)serine-di-n-pentylamide

N-(t-Butyloxycarbonyl)-R-(O-benzyl)serine (3.0 g, 10.15 mmol) wasstirred at 0° C. in 50 mL of CH₂ Cl₂ with BOPCl (2.8 g, 11 mmol) and 2.0mL (1.5 mmol) of TEA. To this reaction mixture was addeddi-n-pentylamine (7 mL, 35 mmol). The mixture was stirred overnight andallowed to warm to room temperature. An additional equivalent of BOPClwas added after 18 hrs and the reaction stirred an additional day atambient temperature. The solvents were evaporated in vacuo and theresidue taken up in EtOAc and washed with water, 1N HCl solution,saturated NaHCO₃, water and then the organic solution was dried overMgSO₄. After filtration and concentration of the titrate in vacuo, theresidue was purified by chromatography using EtOAc-hexane as the elutantsystem in the ratio (1:4). The product was isolated as an oil in 44%yield (1.9 MS(CI) m/e 435(m+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ 0.89(m,6H),1.28(m,8H), 1.4(s,9H), 1.55(m,4H), 3.05-3.2(m,2H), 3.4-3.65(m,4H).4.5(m,2H), 4.85(m,1H), 5.35(d, J=7 Hz,1H), 7.31(m,5H).

Step 17b. R-(O-Benzyl)serine-di-n-pentylamide hydrochloride

The product of example 17a (0.43 g, 1.0 mmol) was dissolved in 4N HCl indioxane (10 mL) and stirred under inert atmosphere (N₂) for an hour.When the reaction was complete by tlc the solvents were evaporated invacuo and hexane and diethylether were added. The residue was trituratedwith these two solvents and the solvents again removed in vacuo. Thisprocedure was repeated several times until the product was obtained as aglassy solid in 93% yield (0.35 g). [a]_(D) =+1.6° (c=0.5, MeOH). MS(CI)m/e 335(m+H)⁺.

Step 17c. N-(3'-Quinolylcarbonyl-R-(O-benzyl)serine-di-n-pentylamide

The hydrochloride salt of example 17b (0.35 g, 0.95 mmol) was stirred in25 mL of CH₂ Cl₂ with NMM, (0.22 mL, 2 mmol) under N₂ at 0° C. EDCI(0.19 g, 1.0 mmol) and HOBt (0.27, 2 mmol) were added followed by theaddition of quinoline-3-carboxylic acid (0.165 g, 0.95 mmol). Thereaction mixture was stirred overnight (warming to ambient temperature).The solvents were evaporated in vacuo and the residue taken up in EtOAcand washed successively with water, saturated NaHCO₃, a saturatedsolution of citric acid, water and brine. The organic solution was driedover MgSO₄ and then filtered. Solvents were evaporated in vacuo and thecrude product subjected to flash chromatography using EtOAc and hexaneas the elutant mixture. The product was crystallized from EtOAc andhexane to provide a semisolid, 0.44 g (94%). [α]_(D) =-4.0° (c=0.45,MeOH). MS(CI) m/e 490(m+H)⁺ . ¹ H NMR(CDCl₃,300 MHz) δ 0.9(m,6H),1.2-1.4(m,SH), 1.5-1.6(m,4H), 3.05-3.28(m,2H), 3.5-3.7(m,2H), 3.8(m,2H),4.57(m,2H), 5.4(m, 1H), 7.3(m,5H), 7.4(d,J=9 Hz,1H), 7.62(dd,J=2,7Hz,1H), 7.81(dd, J=2,7 Hz,1H), 7.9(d,J=8 Hz,1H), 8.15(d,J=9 Hz,1H),8.58(d,J=3 Hz,1H), 9.3(d,J=3 Hz,1H). C,H,N analysis calculated for C₃₀H₃₉ N₃ O₃, 0.75 H₂ O: C 71.61, H 8.11, N 8.35; found: C 71.73, H 8.01, N8.21.

EXAMPLE 18 N-(3'-Quinolylcarbonyl)-R-phenylalanine-di-n-pentylamide Step18a. N-(t-Butyloxycarbonyl)-R-phenylalanine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1butilizing N-(t-Butyloxycarbonyl)-R-phenylalanine (0.8 g, 3.1 mmol),BOPCl (1.2, 4.06 mmol), dipentylamine (3.1 mL, 15 mmol), and TEA (0.4mL, 3.1 mmol). The oily product was isolated in 65.5% yield (0.87 g).[α]_(D) =+7.0° (c=1.0, MeOH). MS(CI) m/e 405(m+H)⁺. ¹ H NMR(CDCl₃,300MHz) δ 0.85(m,6H), 1.15-1.45(m,8H), 1.5(s,9H), 1.55-1.6(m,4H),2.9-3.1(m,5H), 3.5(m,1H), 4.25(m,1H), 5.3(d,J=9 Hz,1H), 7.25(m,5H).

Step 18b. R-Phenylalanine-di-n-pentylamide hydrochloride

The compound was prepared in similar manner to example 1b viadeprotection of N-t-Butyloxycarbonyl-R-phenylalanine-di-n-pentylamide,the product of example 18a, using 4N HCl in dioxane. The product wasisolated in quantitative yield. MS(CI) m/e 305(m+H)⁺.

Step 18c. N-(3'-Quinolylcarbonyl)-R-phenylalanine-di-n-pentylamide

The hydrochloride of example 18b (870 mg, 2.46 mmol), EDCI (550 mg),HOBt (300 mg), and quinoline-3-carboxylic acid (430 mg) were stirred at0° C. under N₂ in 25 mL of anhydrous CH₂ Cl₂. To this mixture was added550 μL of NMM and the mixture was stirred overnight (warming to ambienttemperature). The reaction mixture was poured into EtOAc and water andthe organic solution was separated. The organic extract was washedsuccessively with water, 10% citric acid solution, and saturated aqueousNaHCO₃. The solution was dried over MgSO₄, filtered and concentrated.The residue was purified by chromatography using EtOAc and hexane as theelutant mixture to yield 870 mg of product (77%) after removal of thevolatiles. [α]D=+12.9° (c=1.05, MeOH). MS(CI) m/e 460(m+H)⁺. ¹ HNMR(CDCl₃, 300 MHz) δ 0.9(m,6H), 1.15-1.4(m,8H), 1.5-1.55(m,4H),2.9-3.12 (m,3H), 3.2(m,2H), 3.48-3.6(m,1H), 5.35(m,1H), 7.27(m,5H), 7.48(d,J=10 Hz,1H), 7.62(t,J=8 Hz,1H), 7.8(t,J=8 Hz,1H), 7.9(d,J=9 Hz, 1H),8.15(d,J=9 Hz,1H), 8.55(d,J=3 Hz,1H), 9.38(d,J=3 Hz,1H). C,H,N analysiscalculated for C₂₉ H₃₇ N₃ O₂, 0.5 H₂ O: C 74.32, H 8.39, N 8.97; found:C 73.92, H 8.05, N 8.83.

EXAMPLE 19N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-benzyl)threonine-di-n-pentylamideStep 19a.N-(t-Butyloxycarbonyl)-(2R,3S)-(O-benzyl)threonine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1autilizing N-(t-Butyloxycarbonyl)-D-(O-benzyl)- threonine (5 g, 16.2mmol), BOPCl (8.2 g, 16.2 mmol), dipentylamine (16 mL, 78.5 mmol), andTEA (2.1 mL, 16.2 mmol). The product was isolated in 58% yield (4.15 g).MS(CI)449(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 0.85(t,J=6 Hz,6H), 1.18(d, J=6Hz,3H), 1.2-1.35(m,8H), 1.45(s,9H), 1.5-1.6(m,4H), 3.0-3.18 (m,2H),3.41-3.63(m,2H), 3.75(m,1H), 4.57(dd,J=12,18 Hz,2H), 4.65(m,1H),5.5(d,J=9 Hz,1H), 7.30(m,5H).

Step 19b. (2R,3S)-(O-Benzyl)threonine-di-n-pentylamide hydrochloride

The product of example 19a (1 g, 2.22 mmol) was deprotected and isolatedin a similar manner to that in example 1b. The product was isolated asan oil. [α]_(D) =+13.3° (c=1.1, MeOH). MS(CI) m/e 359(m+H)⁺. ¹ HNMR(DMSO_(d6),300 MHz) δ 0.86(m,6H), 1.08-1.32(m, 11H), 1.48(m,4H),3.03(m,2H), 3.42(m,2H), 3.88(m, 1H), 4.2(d,J=6 Hz,1H), 4.56(m,2H),7.35(m,5H), 8.35(bs,2H).

Step 19c.N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-benzyl)threonine-di-n-pentylamide

The hydrochloride salt of example 19b (0.25 g, 0.65 mmol) was stirred in15 mL of CH₂ Cl₂ with NMM (0.175 mL, 1.3 mmol) under nitrogen at 0° C.EDCI (0.15 g, 0.8 mmol) and HOBt (0.18 g, 1.3 mmol) were added followedby the addition of quinoline-3-carboxylic acid (0.115 g, 0.65 mmol). Thereaction mixture was stirred overnight (warming to ambient temperature).The solvents were evaporated in vacuo and the residue taken up in EtOAcand washed successively with water, saturated NaHCO₃, a saturatedsolution of citric acid, water and brine. The organic solution was driedover MgSO₄ and then filtered. Solvents were evaporated in vacuo and thecrude product subjected to flash chromatography using EtOAc and hexaneas the elutant mixture. The oily product was isolated in 62% yield (0.2g). [α]_(D) =-4.1° (c=1.0, MeOH). MS(CI) m/e 504(m+H)⁺. ¹ HNMR(CDCl₃,300 MHz) δ 0.9(m,6H), 1.2-1.45(m, 11H), 1.5-1.7(m,4H),3.0-3.25(m,2H), 3.56-3.7(m,2H), 3.9(m,1H), 4.5(m,2H), 5.3(apparentq,J=4.5 Hz,1H), 7.2-7.3(m,5H), 7.56(d,J=6 Hz,1H), 7.65(t,J=7 Hz,1H),7.8(t,J=7 Hz,1H), 7.92(d,J=9 Hz,1H) 8.15(d,J=9 Hz,1H), 8.63(d,J=2Hz,1H), 9.35(d,J=3 Hz, 1H). C,H,N analysis calculated for C₃₁ H₄₁ N₃ O₃,1.6 H₂ O: C 69.92, H 7.89, N 8.37; found: C 69.81, H 7.78, N 8.08.

EXAMPLE 20 N-(3'-Quinolylcarbonyl)-(2R,3S)-threonine-di-n-pentylamide

The product of example 19c (1 g, 2 mmol) was stirred in 20 mL of CH₂ Cl₂and 7 mL of borontristrifluoroacetate (1.0M solution in TFA) was addedat 0° C. The mixture was stirred approximately 1 hour The tlc revealedsome starting material therefore another 5 mL ofborontristrifluoroacetate and 5 mL TFA were added. The reactionproceeded overnight to completion by tlc analysis. The reaction mixturewas diluted with MeOH and then concentrated in vacuo. The residue waspurified by chromatography using EtOAc and hexane as the elutantmixture. The pure fractions were pooled together and the desired productcharacterized as the di-TFA salt. mp=84°-6° C. [α]_(D) =-11.6° (c=0.55,MeOH). MS(CI) m/e 414(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 0.85(m,6H),1.13(d,J=7 Hz, 3H), 1.15-1.38(m,8H), 1.48(m,2H), 1.6(m,2H), 3.1(m,1H),3.32-3.53(m,4H), 4.05(m,1H), 4.9(t,J=6 Hz,1H), 7.7(t,J=6 Hz,1H), 7.88(t,J=7 Hz,1H), 8.1(d,J=9 Hz,1H), 8.8(d,J=9 Hz,1H), 8.93(bs,1H), 9.31(bs,1H), 10.02(bs,1H). C,H,N analysis calculated for C₂₄ H₃₅ N₃ O₃, 2 CF₃CO₂ H: C 52.42, H 5.81, N 6.55; found: C52.31, H 5.62, N 6.66.

EXAMPLE 21N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-acetyl)threonine-di-n-pentylamide

Pyridine (20 μL) and acetic anhydride (60 μL) were added to the productof example 20 (51 mg, 0.125 mmol) which was dissolved in acetonitrile (2mL). The reaction mixture was stirred overnight at room temperature.EtOAc was added and this solution was washed successively with water andbrine. The organic solution was dried over MgSO₄. After filtration andconcentration of the filtrate in vacuo, the residue was purified bychromatography using EtOAc and hexane as the elutant system in the ratio(4:1). The product was isolated as a glass in 44% yield (25 mg). MS(CI)m/e 456(m+H)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ 0.9(m,6H), 1.25-1.45(m, 11H),1.52(m,2H), 1.7(m,2H), 2.05(s,3H), 3.1(m,2H), 3.3-3.6 (m,3H),5.28(m,1H), 5.44(m,1H), 7.35(d,J=9 Hz, 1H), 7.65(t,J= 7 Hz,1H),7.82(t,J=7 Hz,1H), 7.95(d,J=7 Hz, 1H), 8.18(d, J=9 Hz,1H), 8.6(d,J=3Hz,1H), 9.35(d,J=3 Hz,1H). C,H,N analysis calculated for C₂₆ H₃₇ N₃ O₄,0.4 H₂ O: C 67.48, H 8.23, N 9.08; found: C 67.69, H 8.20, N 8.60.

EXAMPLE 22N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-methyl)threonine-di-n-pentylamide

Lithium bis(trimethylsilyl)amide in tetrahydrofuran (THF) (0.15 mL of1.0 M solution in THF) was added to a cooled (-10° C.) solution of theproduct of example 20 (55 mg, 0.14 mmol) in 2 mL THF and then methyliodide (0.015 mL) was added. The reaction mixture was stirredapproximately 1 hour and slowly warmed to room temperature. Tlc revealedsome starting material therefore another equivalent of methyl iodide(0.01 mL) was added. The reaction then proceeded to completion by tlc.The reaction mixture was concentrated in vacuo. EtOAc was added to theresidue, which was then washed with water and brine. The EtOAc extractwas dried over MgSO₄. Filtration and concentration of the filtrate invacuo, provided a residue which was purified by chromatography usingEtOAc and hexane as the elutant mixture. An oil was isolated in 47%yield (28 mg). MS(CI) m/e 428(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ0.92(m,6H), 1.25(d, J=6 Hz,3H), 1.25-1.4(m,8H), 1.55-1.6(m,4H),3.05(m,1H), 3.2-3.3 (m,2H), 3.35(s,3H), 3.58-3.82(m,2H), 5.25(m,1H),7.45(d,J=9 Hz, 1H), 7.65(t,J=6 Hz,1H), 7.8(t,J=6 Hz,1H), 7.9(d,J=9Hz,1H), 8.18(d, J=9 Hz,1H), 8.6(d,J=3 Hz,1H), 9.35(d,J=3 Hz,1H).

EXAMPLE 23N-(3'-Quinolylcarbonyl)-3-(2'-thienyl)-R-alanine-di-n-pentylamide Step23a. N-(t-Butyloxycarbonyl)-3-(2'-thienyl)-R-alanine-di-n-pentylamide

N-(t-Butyloxycarbonyl)-R-3-(2'-thienyl)-alanine (0.78 g, 3.25 mmol) wasstirred at 0° C. in 25 mL of CH₂ Cl₂ with BOPCl (0.44 g, 3.25 mmol) and0.5 mL, (3.25 mmol) of TEA. To this reaction mixture was addeddi-n-pentylamine (2 mL, 10 mmol). The mixture was stirred overnight andallowed to warm to room temperature. An additional equivalent of BOPClwas added after 18 hrs and the reactions stirred an additional day atambient temperature. The solvents were evaporated in vacuo and theresidue taken up in EtOAc and washed with water, 1N HCl solution,saturated NaHCO₃ solution, water and then the organic solution was driedover MgSO₄. After filtration and concentration of the titrate in vacuo,the residue was purified by chromatography using EtOAc-hexane as thesolvent system in the ratio (1:4). The product was isolated as an oil in57% yield (0.76 g). [α]_(D) =-2.27° (c=0.66, MeOH). MS(CI) m/e411(m+H)⁺, 355, 311. ¹ H NMR(CDCl₃,300 MHz) δ 0.85(m,6H),1.15-1.38(m,10H), 1.45(s,9H), 1.51(m,2H), 3.1(m,4H), 3.22(m,1H),3.4(m,1H), 4.75 (apparent q,J=10 Hz,1H), 5.45(d,J=9 Hz,1H), 6.83(d,J=6Hz,1H), 6.9(t,J=4 Hz,1H), 7.15(d,J=6 Hz,1H).

Step 23b. R-3-(2'-Thienyl)-alanine-di-n-pentylamide hydrochloride

The product of example 23a (0.22 g, 0.54 mmol) was deprotected andisolated in the same manner as that in example 1b in quantitative yield.MS(CI) m/e 327(M+H)⁺.

Step 23c.N-(3'-Quinolylcarbonyl)-3-(2'-thienyl)-R-alanine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1 cutilizing (80 mg, 0.23 mmol) of the hydrochloride salt of example 23b,quinoline-3-carboxylic acid (40 mg), EDCI (50 mg), HOBt (62 mg), and NMM(51 μL). An oil was isolated in 45% yield, (48 mg). MS(CI) m/e466(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 0.9(m,6H), 1.2-1.4(m,8H),1.45-1.65(m,4H), 3.05-3.4(m,4H), 3.45- 3.6(m,2H), 5.35(dd,J=6,7 Hz,1H),6.87(d,J=3 Hz,1H), 6.94 (m,1H), 7.18(d,J=6 Hz,1H), 7.4(d,J=9 Hz,1H),7.63(dd,J=3,7 Hz,1H), 7.8(dd, J=3,7 Hz,1H), 7.9(d,J=8 Hz,1H), 8.15(d,J=8Hz,1 H), 8.6(d, J=3 Hz,1H), 9.32(d,J=3 Hz,1H). C,H,N analysis calculatedfor C₂₇ H₃₅ N₃ O₂ S, 0.9 H₂ O: C 67.29, H 7.70, N 8.72; found: C67.60, H7.47, N 8.98.

EXAMPLE 24 N-(3'-Quinolylcarbonyl)-S-valine-di-n-pentylamide Step 24a.

N-(t-Butyloxycarbonyl)-S-valine-di-n-pentylamide The reaction andproduct isolation were performed in a similar manner to that in example1a utilizing N-(t-Butyloxycarbonyl)-S-valine (2.5 g, 11.5 mmol), BOPCl(3.5 g, 13.8 mmol) and dipentylamine (11.6 mL, 58 mmol), and TEA (1.6mL, 12 mmol). The oily product was isolated in 55% yield (2.25 g).[α]_(D) =-21.1° (c=1.0, MeOH). MS(CI) m/e 357(m+H)⁺. ¹ H NMR(CDCl₃,300MHz) 8-0.9(m,6H), 1.05(m,6H), 1.25-1.35(m,SH), 1.45(s,9H), 1.5-1.55(m,4H), 1.95(m,1H), 3.0(m,1H), 3.2(m,1H), 3.36(m,1H), 3.6(m,1H),4.4(dt,J=3,7 Hz,1H), 5.24(d,l=9 Hz,1H).

Step 24b. S-Valine-di-n-pentylamide hydrochloride

The product of example 24a (0.2 g, 0.57 mmol) was deprotected and theproduct isolated as in example 1b in quantitative yield. MS(CI) m/e257(m+H)⁺.

Step 24c. N-(3'-Quinolylcarbonyl)-S-valine-di-n-pentylamide

The reaction sequence was performed in a similar manner to that inexample 1c utilizing 175 mg of the hydrochloride salt of example 24b,quinoline-3-carboxylic acid (110 mg), EDCI (125 mg), HOBt (165 mg), andNMM (75 μL). The glassy product was isolated in 80% yield, (198 mg).[α]_(D) =+12.95° (c=0.8, MeOH). MS(CI) m/e 412(m+H)¹. ¹ H NMR(CDCl₃,300MHz) δ 0.8-1.05 (m,12H), 1.2-1.44(m,8 H), 1.55(m,4H), 2.15(m,1H),3.1(m,1H), 3.3 (m,1H), 3.5(m,1H), 3.65(m,1H), 5.1(dd,J=3,6 Hz,1H),7.25(d,J=7 Hz, 1H), 7.62(t,J=7 Hz,1H), 7.8(t,J=7 Hz,1H), 7.9(d,J=8Hz,1H), 8.15(d, J=9 Hz,1H), 8.61(d,J=3 Hz,1H), 9.35(d,J=3 Hz,1H). C,H,Nanalysis calculated for C₂₅ H₃₇ N₃ O₂, 0.25 H₂ O: C72.16, H 9.09, N10.10; found: C 72.41, H 9.21, N 9.97.

EXAMPLE 25 N-(2'-Indolylcarbonyl)-R-histidine-di-n-pentylamide Step 25a.N-(t-Butyloxycarbonyl)-(N^(im) -tosyl)-R-histidine-di-n-pentylamide

N-(t-Butyloxycarbonyl)-R-(N^(im) -tosyl)-histidine, (4.95 g, 12.6 mmol)was stirred at 0° C. in 50 mL of CH₂ Cl₂ with BOPCl (3.2 g, 12.6 mmol)and 1.65 mL (12.6 mmol) TEA. To this reaction mixture was addeddi-n-pentylamine (7.7 mL, 38 mmol). The mixture was stirred overnightand allowed to warm to room temperature. An additional equivalent ofBOPCl was added after 18 hrs and the reaction stirred an additional dayat ambient temperature. The solvents were evaporated in vacuo and theresidue was taken up in EtOAc and washed with water, 1N HCl solution,saturation NaHCO₃, water. The organic solution was dried over MgSO₄.After filtration and concentration of the filtrate in vacuo, the residuewas purified by chromatography using EtOAc-hexane as the solvent systemin the ratio (1:4). The product was isolated as an oil in 75% yield (5.1g). [α]_(D) =+8.8° (c=1.0, MeOH). MS(CI) m/e 549(m+ H)⁺. ¹ HNMR(DMSO_(d6), 300 MHz) δ 0.85(m,6H), 1.05-1.46(m,21H), 2.42(s,3H),2.67(m,2H), 3.03-3.15(m,4H), 4.52(m,1H), 7.0(s,1H), 7.28(d,J=7 Hz,1H),7.49(d, J=7 Hz,2H), 7.9(d,J=7 Hz,2H), 8.28(s,1H). C,H,N analysiscalculated for C₂₈ H₄₄ N₄ O₅ S: C 61.28, H 8.08, N 10.21; found: C61.04, H 8.05, N 10.10.

Step 25b. (N^(im) -Tosyl)-R-histidine-di-n-pentylamide

To a solution of the product of example 25a (6.7 g, 12.21 mmol) in CH₂Cl₂ (100 mL) was added TFA (40-50 mL). The reaction mixture was stirredat room temperature 60 minutes. When reaction was complete by tlc, thesolvents were evaporated several times in vacuo and CH₂ Cl₂ was addedwith a saturated solution of NaHCO₃. The reaction mixture was stirredvigorously another 1 hr and after separation of layers, the organiclayer was washed several times with water and brine. The CH₂ Cl₂ layersand washings were dried over MgSO₄. The product was then concentrated invacuo. The semisolid product was isolated and dried in a vacuum ovenover P₂ O₅ at room temperature, 5.1 g (93% yield). [α]_(D) =-9.4°(c=1.0, MeOH). MS(CI) m/e 449(m+H)⁺, 264, 295. ¹ H NMR(CDCl₃, 300 MHz) δ0.85(m,6H), 1.1-1.35(m,8H), 1.47-1.6(m,4H), 2.45(s,3H), 2.9-3.2(m,6H),3.4-3.55(m,2H), 4.5(m,1H), 7.18(s,1H), 7.35(d,J=8 Hz,2H), 7.82(d,J=8Hz,2H), 7.95(s,1H).

Step 25c. N-(2'-Indolylcarbonyl)-R-histidine-di-n-pentylamide

The compound of example 25b (170 mg, 0.5 mmol), EDCI (105 mg), HOBt (135mg) and indole-2-carboxylic acid (85 mg) were stirred at 0° C. undernitrogen in 10 mL of anhydrous CH₂ Cl₂. To this mixture was added 110 μLof NMM and the mixture was stirred overnight (warming to ambienttemperature). The reaction mixture was poured into EtOAc and water andthe organic extract was washed successively with water, 10% citric acidsolution, and saturated aqueous NaHCO₃. The solution was dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography using chloroform (CHCl₃)/MeOH/ammonia as the elutantmixture to provide 98 mg of the semisolid product (45% yield) afterevaporation of the volatiles. [α]_(D) =+9.8° (c=0.46, MeOH). MS(CI) m/e438(m+H)⁺, 253, 281. ¹ H NMR (CDCl₃, 300 MHz) δ 0.75-0.95(m,6H), 1.2(m,8H), 1.5(m,4H), 3.13 (m,4H), 3.3(m,1H), 3.4(m,1H), 3.5(m,2H),5.32(m,1H), 6.8(s,1H), 6.9(s,1H), 7.1(t,J=7 Hz,2H), 7.2(t,J=7 Hz,2H),7.35(d,J=9 Hz,1H), 7.59 (d,J=9 Hz, 1H), 9.8(s,1H). C,H,N analysiscalculated for C₂₅ H₃₅ N₅ O₂, 0.5 H₂ O: C 67.23, H 8.13, N 15.68; found:C 67.24 H 8.06, N 15.24.

EXAMPLE 26 N.sup.α -(3'-Quinolylcarbonyl)-N.sup.ε-(benzyloxycarbonyl)-R-lysine-di-n-pentylamide Step 26a. N.sup.α-(t-Butyloxycarbonyl)-N.sup.ε-(benzyloxycarbonyl)-R-lysine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1autilizing N.sup.α -t-Butyloxycarbonyl-R-(N.sup.ε-benzyloxycarbonyl)Lysine (5 g, 13.15 mmol), BOPCl (6.7 g, 26.3 mmol),di-n-pentylamine (26 mL, 131 mmol) and TEA (1.8 mL, 13.5 mmol) in CH₂Cl₂ (25 mL). The oily product was isolated in 64.5% yield (4.4 g).[α]_(D) =+65.3° (c=0.15, MeOH). MS(CI) m/e 520(m+H)⁺. ¹ H NMR(CDCl₃,300MHz) δ 0.9(m,6H), 1.2-1.35(m, 12H), 1.41(s,9H), 1.5-1.66(m,4H),3.05-3.25(m,4H), 3.3(m,2H), 3.5(m,2H), 4.53(m,1H), 4.9(m,1H), 5.1(s,2H),5.38(d,J=9 Hz,1H), 7.3(m,5H).

Step 26b. N.sup.ε -(Benzyloxycarbonyl)-R-lysine-di-n-pentylamidehydrochloride

The compound was prepared in similar manner to example 1b viadeprotection of the product of example 26a using 4N HCl in dioxane. Theproduct was isolated in quantitative yield. MS(CI) m/e 420(m+H)⁺.

Step 26c. Nα-(3'-Quinolylcarbonyl)-N.sup.ε -(benzyloxycarbonyl)-R-lysinedi-n-pentylamide

The reaction was performed in the similar manner to that in example 1cutilizing 1.0 g of hydrochloride salt of example 26bquinoline-3-carboxylic acid (0.38 g), EDCI (0.45 g), HOBT (0.6 g), andNMM (0.48 mL). The oily product was isolated in 72% yield. [α]_(D)=+2.7° (c=0.7, MeOH). MS(CI) m/e 575(m+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ0.9(m,6H), 1.3-1.62(m,8H), 1.53(m,6H), 1.65(m, 2H), 1.85(m,2H),3.05-3.55(m,1H), 5.05(m,11H), 5.15(m,2H), 7.28 (m,5H), 7.55(t,J=8Hz,1H), 7.8(m,3H), 8.18(d,J=9 Hz,1H), 8.58(d, J=2 Hz,1H), 9.32(d,J=2Hz,1H). C,H,N calculated for C₃₄ H₄₆ N₄ O₄ : C 71.05, H 8.07, N 9.75;found: C 71.00, H 8.18, N 9.68.

EXAMPLE 27 N-(3'-Quinolylcarbonyl)-3-(1'-Naphthyl)-R-alanine-di-n-pentylamide Step 27a.N-(t-Butyloxycarbonyl)-3-(1'-naphthyl)-R-alanine-di-n-pentylamine

N-(t-Butyloxycarbonyl)-3-(1'-naphthyl)-R-alanine (0.35 g, 1.1 mmol) wasstirred at 0° C. in 25 mL of CH₂ Cl₂ with BOPCl, (0.3 g, 1.2 mmol), and0.15 mL of TEA (1.2 mmol). To this reaction mixture was addeddi-n-pentylamine (0.8 mL, 4 mmol). The mixture was stirred overnight andallowed to warm to room temperature. An additional equivalent of BOPClwas added after 18 hrs and the reaction stirred an additional day atambient temperature. The solvents were evaporated in vacuo and theresidue taken up in EtOAc and washed with water, 1N HCl solution,saturated NaHCO₃, water and then the organic solution was dried overMgSO₄. After filtration and concentration of the titrate in vacuo, theresidue was purified by chromatography using EtOAc-hexane as the solventsystem in the ratio (1:4). The product was isolated as an oil in 65%yield (0.25 g). MS(CI) m/e 455(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) α0.7-0.8(m,6H), 0.9(m,8H), 1.2-1.3(s,4H), 1.35(s,9H), 3.0(m,2H),3.35(m,2H), 3.5-3.6(m,2H), 4.3(m,1H), 7.4(m,1H), 7.45-7.55(m,2H),7.6(m,1H), 7.8 (d,J=9 Hz, 1H), 7.85(d,J=9 Hz,1H), 8.35(d,J=9 Hz,1H),8.9(bs,1H).

Step 27b. 3-(1 '-Naphthyl)-R-alanine-di-n-pentylamide hydrochloride

The product of example 27a (0.32 g, 0.72 mmol) was dissolved in 4N HClin dioxane (10 mL) and stirred under inert atmosphere (N₂) for an hour.When the reaction was complete by tlc the solvents were evaporated invacuo and hexane and diethylether added. The residue was triturated withthese two solvents until the product was obtained as a glassy solid inquantitative yield. MS(CI) m/e 391(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz): δ0.63(m,3H), 0.85(m,3H), 1.05-1.45(m,10H), 1.5-1.72(m,2H), 2.62(m,1H),2.85(m,1H), 3.6-3.92(m,4H), 4.85(m,1H), 4.73(m,2H), 7.36(m,1H),7.5(m,1H), 7.7(d,J=6 Hz,1H), 7.75(d,J=6 Hz,1H), 8.35(d,J=8 Hz,1H),8.92(bs,2H), 9.4(s,1H).

Step 27c.N-(3'-Quinolylcarbonyl)-3-(1'-Naphthyl)-R-alanine-di-n-pentylamide

The hydrochloride of example 27b (200 mg, 0.52 mmol), EDCI, HOBt (70 mg)and quinoline-3-carboxylic acid (90 mg) were stirred at 0° C. under N₂in 5 mL of anhydrous CH₂ Cl₂. To this mixture was added 10 μL of NMM andthe mixture was stirred overnight (warming to ambient temperature). Thereaction mixture was poured into EtOAc and water and then the separatedorganic extract was washed successively with water, 10% citric acidsolution, and saturated aqueous NaHCO₃. The solution was dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography using EtOAc and hexane as the elutant mixture to provide180 mg of the oily product (68% yield) after removal of the volatiles.MS(CI) m/e 510(m+H)⁺, 280. 1H NMR(CDCl₃,300 MHz) δ 0.72(m,3H),0.9(m,3H), 1.1-1.45(m,10H), 1.5.1-6(m,2H), 2.38-2.6(m,2H), 2.85(m,1H),3.47(m,2H), 3.9(m,1H), 5.6(m,1H), 7.35(d,J=6 Hz,2H), 7.52(t,J=7 Hz,2H),7.6-7.7(m,3H), 7.72-7.93(m,3H), 8.15(d,J=9 Hz,1H) 8.55(d,J=9 Hz,1H),8.6(d,J=3 Hz,1H), 9.4(d,J=3 Hz,1H).

EXAMPLE 28N-(3'-Quinolylcarbonyl)-3-(2'-Naphthyl)-R-alanine-di-n-pentylamide Step28a. N-(t-Butyloxycarbonyl)-3-(2'-naphthyl)-R-alanine-di-n-pentylamide

N-(t-Butyloxycarbonyl)-3-(2'-naphthyl)-R-alanine (0.31 g, 1.0 mmol) wasstirred at 0° C. in 25 mL of CH₂ Cl₂ with BOPCl, (0.38 g, 1.5 mmol) and0.2 mL of TEA (1.5 mmol). To this reaction mixture was addeddi-n-pentylamine (0.7 mL, 3.5 mmol). The mixture was stirred overnightand allowed to warm to room temperature. An additional equivalent ofBOPCl was added after 18 hrs and the reaction stirred an additional dayat ambient temperature. The solvents were evaporated in vacuo and theresidue taken up in EtOAc and washed with water, 1N HCl solution,saturated NaHCO₃, and water. The organic solution was dried over MgSO₄.After filtration and concentration of the filtrate in vacuo, the residuewas purified by chromatography using EtOAc-hexane as the solvent systemin the ratio (1:4). The product was isolated as an oil in 62% yield(0.28 g). MS(CI) m/e 455(m+H)⁺, 355.

Step 28b. 3-(2'-Naphthyl)-R-alanine-di-n-pentylamide hydrochloride

The product of example 28a (0.28 g, 0.6 mmol) was dissolved in 4N HCl indioxane (10 mL) and stirred under N₂ for an hour. When the reaction wascomplete by tlc the solvents were evaporated in vacuo and then hexaneand diethylether were added. The residue was triturated with these twosolvents until the product was obtained as a glassy solid in 93% yield.MS(CI) m/e 355(m+H)⁺.

Step 28c.N-(3'-Quinolylcarbonyl)-3-(2'-Naphthyl)-R-alanine-di-n-dipentylamide

The reaction was performed in a similar manner to that in example 1cutilizing 75 mg of hydrochloride salt of example 28b,quinoline-3-carboxylic acid (34 mg), EDCI (40 mg), HOBt (50 mg), and NMM(22 μL). The oily product was isolated in 31% yield, (32 mg). MS(CI) m/e510 (m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 0.85(m,6H), 1.06-1.35 (m,12H),2.85(m,1H), 3.0(m,2H), 3.35(m,2H), 3.55(m,1H), 5.45(apparent q,J=7Hz,1H), 7.32-7.5(m,4H), 7.62(t, J=6 Hz,1H), 7.68-7.82(m,5H), 7.88(d,J=7Hz,1H), 8.15(d,J=7Hz, 1H), 8.52(d,J=2 Hz,1H).

EXAMPLE 29 N-(3'-Quinolylcarbonyl)-R-histidine-di-n-pentylamide

The free base of example 25b (3.7 g, 9.26 mmol), EDCI, (1.7 g, 9 mmol),HOBt (3.65 g) and 1.5 g quinoline-3-carboxylic acid were stirred at 0°C. in 50 mL of anhydrous dimethylformamide (DMF) and CH₂ Cl₂ in 1:1ratio. After reaction was complete by tlc, solvents were evaporatedunder vacuum and the residue dissolved in large excess of EtOAc (300mL). Water was added and the organic extract was washed with 10% citricacid solution, and saturated NaHCO₃. The solution was dried over MgSO₄,filtered and concentrated. The residue was purified by chromatographyusing CHCl₃ -MeOH arid ammonium hydroxide as the elutant mixture toprovide 1.98 g (68.3%) product. [α]D=-6.4° (c=0.25, MeOH). MS(CI) m/e450(m+H)⁺, 156. ¹ H NMR (CDCl₃,300 MHz) δ 0.9(m,6H), 1.29(m,8H),1.45-1.6(m, 4H), 3.08-3.2(m,3H), 3.23-3.4(m,2H), 3.5-3.6(m,1H),5.3(apparent q,J=9 Hz, 1H), 6.85(s,1H), 7.6(m,3H), 7.(t,J=6H,1H),7.88(d,J=8 Hz,1H), 7.97(d, J=8 Hz,1H), 8.15(d,J=5 Hz,1H), 8.6(d,J=3Hz,1H), 9.3(d,J=3 Hz,1H). N-(3'-Quinolylcarbonyl)-(N^(im)-tosyl)-R-histidine-di-n-pentylamide (0.2 g) also was isolated refer toexample 30.

EXAMPLE 30 N-3'-Quinolylcarbonyl-(N^(im)-tosyl)-R-histidine-di-n-pentylamide

The title compound of example 30 was isolated as a side product in theprocedure in example 29. [α]_(D) =+13.3° (c=1.05, MeOH). MS(CI) m/e604(m+H)⁺, 450. ¹ H NMR(CDCl₃,300 MHz) δ 0.9(m,6H), 1.3(m,8H),1.45-1.7(m,4H), 2.25(s,3H), 3.0-3.13(m,3H), 3.25(m,1H), 3.35(m,1H),3.5(m,1H), 5.36(apparent q,J=6 Hz,1H), 7.15(m,3H), 7.6(t,J=7 Hz,2H),7.7(d,J=9 Hz,2H), 7.8-7.9(m,2H), 7.95(d,J=2 Hz,1H), 8.13(d,J=7 Hz,1H),8.45(d,J=3 Hz,1H), 9.18(d, J=3 Hz,1H). C,H,N analysis calculated for C₃₃H₄₁ N₅ O₄ S: C 65.64, H 6.85, N 11.60; found: C 65.58, H 6.84, N 11.50.

EXAMPLE 31 N-(3'-Quinolylcarbonyl)-R-lysine-di-n-pentylamide

To a suspension of 0.5 g 10% Pd/C in MeOH (25 mL) and cyclohexadiene (3mL) under N₂ was added a solution of the product of example 26c (0.51 g,0.89 mmol) in MeOH via cannula. The reaction mixture was stirredovernight at ambient temperature. Cyclohexadiene (2 mL) was added andthe reaction was continued overnight. The mixture was filtered throughcelite and washed several times with MeOH. The flitrate and washingswere combined and concentrated in vacuo. The residue was subjected toflash chromatography using CHCl3-MeOH and ammonium hydroxide 90:10:1 asthe elutant mixture. Lyophilization provided product in 64% yield (0.25g). MS(CI) m/e 441(m+H)⁺. ¹ H NMR(DMSO_(d6),300 MHz) δ 0.85(m,6H),1.15-1.35(m,8H), 1.4-1.65(m,4H), 1.7(m,2H), 1.75(m,2H), 2.7(m,2H),3.1-3.5(m,8H), 4.9(m,1H), 7.7(t,J=6 Hz,1 H), 7.88(t,J=6 Hz,1H),8.1(d,J=8 Hz,2H), 8.9(d,J=3 Hz,1H), 9.0(d,J=3 Hz,1H), 9.3(d,J=3 Hz,1H).C,H,N analysis calculated for C₂₆ H₄₀ N₄ O₂, H₂ O: C 69.45, H 8.97, N12.46; found: C 69.48, H 8.76, N 12.03.

EXAMPLE 32N-(3'-Quinolylcarbonyl)-R-(4'-hydroxyphenyl)glycine-di-n-pentylamideStep 32a.N-(t-Butyloxycarbonyl)-R-(4'-Hydroxyphenyl)glycine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1autilizing N-(t-Butyloxycarbonyl)-R-4'-hydroxy phenylglycine (5 g, 18.7mmol), BOPCl (5.1 g, 20 mmol), dipentylamine (8 mL, 37 mmol), and TEA(2.6 mL). The product was isolated in 78% yield (5.9 g). MS(CI) m/e407(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 0.85(m,6H), 1.1-1.35(m,8H),1.3(s,9H), 1.45-1.58(m,4H), 3.0(m,1H), 3.15(m,2H), 3.45(m,1H),5.42(d,J=9 Hz,1H), 6.02(d,J=9 Hz,1H), 6.5(s,1H), 6.75(d,J=9 Hz,2H),7.18(d,J=9 Hz,2H).

Step 32b. R-(4'-Hydroxyphenyl)-glycine-di-n-pentylamide hydrochloride

The compound was prepared in similar manner to example 1b viadeprotection of the product of example 32a, using 4N HCl in dioxane. Theoily product was isolated in 90% yield. [α]_(D) =-87.0° (c=0.2, MeOH).MS(CI) m/e 307(m+H)⁺. ¹ H NMR(DMSO_(d6), 300 MHz) δ 0.82(m,6H),1.02-1.2(m,8H), 1.3-1.5(m,4H), 3.05-3.3(m,2H), 3.32-3.4(m,2H),5.22(bs,1H), 6.83(d,J=9 Hz,2H), 7.25(d,J=9 Hz,2H), 8.4(bs,3H).

Step 32c.N-(3'-Quinolylcarbonyl)-R-(4'-hydroxyphenyl)glycine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 1cutilizing (300 mg, 2.6 mmol) of hydrochloride salt of example 32b,quinoline-3-carboxylic acid (450 mg), EDCI (550 mg), HOBt (380 mg), andNMM (0.62 mL). Product was isolated in 53% yield (0.78 g). mp=79°-80° C.[α]_(D) =-99.6° (c=1.0, MeOH). MS(CI) m/e 462(m+H)⁺. ¹ H NMR(CDCl₃,300MHz) δ 0.85(t,J=7 Hz, 6H), 1.1-1.3(m,10H), 1.4-1.5(m,2H), 3.1-3.2(m,2H),3.25-3.5 (m,2H), 5.9(d,J=9 Hz,1H), 6.6(d,J=9 Hz,2H), 7.25(d,J=9 Hz,2H),7.7(t,J=7 Hz,1H), 7.85(t,J=7 Hz,1H), 8.08(d,J=9 Hz,2H), 8.9(d,J=3 Hz,1H), 9.1(d,J=6 Hz,1H), 9.25(d,J=3 Hz,1H), 9.53(s,1H). C,H,N analysiscalculated for C₂₈ H₃₅ N₃ O₃ : C 72.85, H 7.64, N 9.10; found: C 72.65,H 7.65, N 9.08.

EXAMPLE 33 N-(8'-Hydroxy-2'-quinolylcarbonyl)-R-valine-di-n-pentylamide

The title compound was prepared in a similar fashion to that in example1c. mp=143°-4° C. MS(CI) m/e 428(m+H)⁺, 243, 158. ¹ H NMR(CDCl₃,300 MHz)δ 8.58(d,J=10 Hz,1H), 8.31(s,2H), 8.09(s,1H), 7.54(m,1H), 7.39(dd,J=1,8Hz,1H), 7.24(m,1H), 5.01(dd,J=7,10 Hz, 1H), 3.65(dt,J=7,16 Hz,1H),3.28-3.55(m,2H), 3.06(dt,J=7,14 Hz,1H), 2.22(septet,J=7 Hz,1H),1.50-1.75(m,4H), 1.25-1.42(m,8H), 1.06(d,J=7 Hz,3H), 1.03(d,J=7 Hz,3H),0.92(t,J=7 Hz,3H), 0.89(t,J=7 Hz,3H). C,H,N analysis calculated for C₂₅H₃₇ N₃ O₃, 0.1 H₂ O: C 69.93, H 8.73, N 9.79; found: C 69.78, H 8.51, N9.61.

EXAMPLE 34 N-(2'-Methylphenylaminocarbonyl)-R-valine-di-n-pentylamide

A solution of hydrochloride of example 1b (0.15 g, 0.52 mmol),2-methyl-phenylisocyanate (0.1 g) and TEA (0.1 mL) was allowed to reactat ambient temperature. The solvent was removed in vacuo and the residuedissolved in EtOAc. Water was added and the mixture extracted severaltimes with EtOAc. The combined EtOAc extracts were washed with brine anddried over MgSO₄. The volatiles were removed in vacuo and the residuepurified by chromatography. The oily product was isolated in 80% yield.1.5° (c=0.4, MeOH). MS(CI) m/e 390(m+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ0.8-1.0(m,12H), 1.12-1.41(m,8H), 1.42-1.78 (m,4H), 2.01(m,1H),2.22(s,3H), 3.25(m,1H), 3.35(m,2H), 3.51(m, 1H), 4.7(m,1H), 6.5(m,1H),6.7(s,1H), 7.04(t,J=6 Hz,1H), 7.16(m,2H), 7.53(d,J=9 Hz,1H). C,H,Nanalysis calculated for C₂₃ H₃₉ N₃ O₂ : C 70.91, H 10.09, N 10.79;found: C 70.57, H 9.46, N 10.57.

EXAMPLE 35 N.sup.α -(3'-Quinolylcarbonyl)-N.sup.ε-(2'-Chlorobenzyloxycarbonyl)-R-lysine-di-n-pentylamide Step 35a.N.sup.α -(t-Butyloxycarbonyl)-N⁻⁶⁸(2'-Chlorobenzyloxycarbonyl)-R-lysine-di-n-pentylamide

N.sup.α -(t-Butyloxycarbonyl)-N.sup.ε-(2'-chlorobenzyloxycarbonyl)-R-lysine (1.0 g, 2.4 mmol) was stirred at0° C. in 25 mL of CH₂ Cl₂ with BOPCl, (0.65 g, 2.6 mmol), and TEA (0.35mL, 2.4 mmol). To this reaction mixture was added di-n-pentylamine (2.5mL, 12 mmol). The mixture was stirred overnight and allowed to warm toroom temperature. An additional equivalent of BOPCl was added after 18hrs and the reaction stirred an additional day at ambient temperature.The solvents were evaporated in vacuo and the residue taken up in EtOAcand washed with water, 1 N HCl soution, saturated NaHCO₃, and water. Theorganic solution was dried over MgSO₄. After filtration andconcentration of the filtrate in vacuo, the residue was purified bychromatography using EtOAc-hexane as the solvent system in the ratio(1:4). The product was isolated as an oil in 53% yield (0.7 g). MS(CI)m/e 554(m+H)⁺, 326. .sup. 1 H NMR(CDCl₃,300 MHz) δ 0.9(m,6H), 1.2-1.38(m,12H), 1.42(s,9H), 1.5-1.7(m,4H), 3.02-3.45(m,4H), 3.48(m,4H),4.5(m,1H), 5.01(m,1H), 5.2(s,2H), 5.4(d,J=9 Hz,1H), 7.25(m,2H),7.3-7.45(m,2H).

Step 35b. N.sup.ε-(2'-Chlorobenzyloxycarbonyl)-R-lysine-di-n-pentylamide hydrochloride

The compound was prepared in similar manner to example 1b viadeprotection of the product of example 35a, using 4 N HCl in dioxane.The product was isolated in quantitative yield. MS(CI) m/e 454(m+H)⁺,free base.

Step 35c. N.sup.ε -(3'-Quinolylcarbonyl)-N.sup.ε-(2'-chlorobenzyloxycarbonyl)-R-lysine-di-n-pentylamide

The hydrochloride salt of example 35b (0.5 g, 1.02 mmol) was stirred in15 mL of CH₂ Cl₂ with NMM (0.24 mL, 2.2 mmol) under N₂ at 0° C. EDCI(0.25 g, 1.3 mmol) and HOBt (0.3 g, 2.2 mmol) were added followed by theaddition of quinoline-3-carboxylic acid (0.1 g, 1.1 mmol). The reactionmixture was stirred overnight and allowed to slowly warm to ambienttemperature. The solvents were evaporated in vacuo and the residue takenup in EtOAc and washed successively with water, saturated NaHCO₃, asaturated solution of citric acid, water and brine. The organic solutionwas dried over MgSO₄ and then filtered. Solvents were evaporated invacuo and the crude product subjected to flash chromatography usingEtOAc and hexane as the elutant mixture. The product was isolated as anoil, 0.46 g (74%). MS(CI) m/e 609(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ0.8-0.96(m,6H) 1.16-1.42(m,12H), 1.45-1.6(m,2H), 1.8-2.0(m,2H),2.7(m,2H), 3.07-3.45(m,4H), 3.5-3.65(m,2H), 5.15(m,3H), 6.85(d,J=12Hz,1H), 7.2 (d,J=9 Hz,2H), 7.4(d,J=9 Hz,2H), 7.6(m,2H), 7.8(t,J=7Hz,1H), 7.9(t, J=7 Hz,1H), 8.15(d,J=9 Hz,1H), 8.6(s,1H), 9.35(d,J=3Hz,1H). C,H,N analysis calculated for C₃₄ H₄₅ ClN₄ O₄, 0.6 H₂ O: C65.86, H 7.41, N 9.04; found: C 65.63, H 7.29, N 9.42.

EXAMPLE 36 N.sup.α -(3'-Quinolylcarbonyl)-N.sup.ε-(acetyl)-R-lysine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 21utilizing 60 mg of the product of example 31 and pyridine with aceticanhydride. The oily product was purified by standard chromatography andisolated in 33% yield (22 mg). [α]_(D) =-1.3° (c=0.5, MeOH). MS(CI) m/e483(m+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ 0.92(m,6H), 1.23-1.4(m,8H),1.45-1.7(m,8H), 1.8(m,2H), 1.98(s,3H), 3.1(m,1H), 3.25(m,2H),3.32(m,1H), 3.6 (m,2H), 5.15(m,1H), 5.85(bs,1H), 7.5(d,J=8 Hz,1H),7.65(t,J=6 Hz, 1H), 7.82(t,J=6 Hz,1H), 7.94(d,J=8 Hz,1H), 8.18(d,J=8Hz,1H), 8.62(d, J=2 Hz,1H), 9.36(d,2 Hz,1H).

EXAMPLE 37 N-(5'-Hydroxyindolyl-2'-carbonyl)-R-valine-di-n-pentylamide

The 5-hydroxyindole-2-carboxylic acid (95 mg), hydrochloride of example1b (150 mg), NMM (0.12 mL), HOBt (70 mg), and EDCI (105 mg) reactedunder similar conditions to those described in example 1c. The productwas isolated in 74% yield. MS(CI) m/e 416(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz)δ 0.9(m,6H), 1.0(apparent q,J=7 Hz,6H), 1.32(m,8H), 1.62(m,4H),2.11(m,1H), 3.15(m,1H), 3.2(m,1H), 3.43(m,1H), 3.62(m,1H), 4.95(m,1H),5.6(s,1H), 6.78(m, 1H), 6.88(dd,J=2,9 Hz,1H), 6.98(d,J=9 Hz,1H),7.02(d,J=2 Hz, 1H), 7.25(d,J=9 Hz,1H), 9.3(s,1H).

EXAMPLE 38 N.sup.α -(3'-Quinolylcarbonyl)-N.sup.ε-[E-3'-(4"-chlorophenyl)prop-2'-enoyl]-R-lysine-di-n-pentylamide Step38a. 4-Chlorocinnamic acid N-hydroxysuccinimide ester

To a solution of 4-chlorocinnamic acid (0.8 g, 4.38 mmol) in CH₂ Cl₂ wasadded N-hydroxysuccinimide (0.55 g, 4.8 mmol) and EDCI and the reactionmixture was stirred at ambient temperature overnight. The solvents wereremoved in vacuo and the residue dissolved in EtOAc and water. CombinedEtOAc extracts were dried over MgSO₄ and the solution concentrated invacuo. The residue was crystallized from a mixture of EtOAc and hexane.The product was isolated in 72% yield (0.88g). mp=192°-193° C. MS(CI)m/e 297(m+NH₄ ⁺). ¹ H NMR(DMSOd_(d6),300 MHz) δ 2.87(s,4H), 7.05(d,J=17Hz,1H), 7.56(d,J=9 Hz,2H), 7.92(d,J=9 Hz,2H), 7.99(d,J=17 Hz,1H).

Step 38b. N.sup.α -(3'-Quinolylcarbonyl)-N.sup.ε-[E-3'-(4"-Chlorophenyl)prop-2'-enoyl]-R-lysine-di-n-pentylamide

To a solution of example 31 (60 mg, 0.14 mmol) in DMF (8 mL) cooled to0° C. were added NMM (35 μL) and the active ester of example 38a (40mg,0.14 mmol). The mixture was stirred overnight with warming to ambienttemperature. The DMF was removed in vacuo and the residue waschromatographed on silica using EtOAc-hexane as the elutant mixture. Theoily product was isolated in 40% yield (35 mg). MS(CI) m/e 605(m+H)⁺. ¹H NMR (CDCl₃,300 MHz) δ 0.92(m, 6H), 1.3(m,8H), 1.62(m,8H), 1.83(m,2H),3.14(m,1H), 3.35(m,4H), 3.58(m,1H), 5.15(m,1H), 6.18(m,1H), 6.35 (d,J=17Hz,1H), 7.25(m, 6H), 7.48(d,J=17 Hz,1H), 7.62(t,J=8 Hz,1H), 7.83(t,J= 8Hz,1H), 8.15(d,J=9 Hz,1H), 8.62(d,J=2 Hz,1H), 9.37(d,J=2 Hz, 1H).

EXAMPLE 39 N,O-Di-(3'-Quinolylcarbonyl)-R-tyrosine-di-n-pentylamide Step39a. N-(t-Butyloxycarbonyl)-R-tyrosine-di-n-pentylamide

N-t-Butyloxycarbonyl-R-tyrosine (4.5 g, 15.4 mmol) was stirred withBOPCl (3.92 g, 15.4 mmol) and dipentylamine (7.9 mL, 39 mmol) in 100 mLof THF at 4° C. and allowed to warm to room temperature overnight. Afterone day, additional BOPCl (800 mg) was added and, after two days, thevolatiles were evaporated. The residue, dissolved in EtOAc, wasextracted with 0.1M citric acid solution, 0.1M sodium carbonate (Na₂CO₃) solution, and water; then dried over MgSO₄, filtered andconcentrated in vacuo to yield an oil, 5.67 g, 13.4 mmol (87.4%). R_(f)=0.45 (2:1 hexanes-EtOAc). [α]_(D) =+2.8° (c=0.76, MeOH). MS(CI) m/e421(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 0.88(apparent q,J=7 Hz,6H),1.15-1.32(m, 10H), 1.36-1.47(m,11H), 2.80-3.07(m,5H), 3.38-3.48 (m,1H),4.72 (apparent q,J=6 Hz,1H), 5.41(d,J=8 Hz,1H), 6.70(d,J=8 Hz,2H),7.02(d, J=8 Hz,2H).

Step 39b. R-Tyrosine-di-n-pentylamide hydrochloride

The product of example 39a (2.0 g, 4.75 mmol) was dissolved in 4N HCl indioxane (20 mL, 80 mmol) that was precooled to 4° C. After 3 hours, theexcess reagent was evaporated and the oily residue was placed under highvacuum overnight to yield a glass, 1.5 g, 4.2 mmol (87%). [α]_(D)=-42.8° (c=1.2, MeOH). MS(CI) m/e 321 (m+H)⁺. ¹ H NMR(DMSO_(d6),300 MHz)δ 0.82-0.89(m,6H), 1.1-1.4(m,12H), 2.70-3.04(m,5H), 3.37-3.50(m,1H),4.22(dd,J=5,7 Hz, 1H), 6.70(d,J=8 Hz,2H), 6.99(d,J=8 Hz,2H),8.37(bs,3H), 9.48(s,1H).

Step 39c. N,O-Di-(3'-Quinolylcarbonyl)-R-tyrosine-di-n-pentylamide

The product of example 39b (357 mg, 1 mmol), quinoline-3-carboxylic acid(173 mg, 1 mmol), HOBt (13 mg, 0.1 mmol), and TEA (279 μL, 2 mmol) weredissolved in 10 mL CH₂ Cl₂ and EDCI (191 mg, 1 mmol) was then added inone portion. After 3 days, the volatiles were evaporated and theresidue, in EtOAc, was extracted as in example 41a. The residue was thenpurified by chromatography on silica gel eluted with 1% ethanol (EtOH)in CHCl₃ to provide first the mono-acylated material (19 mg, see example46) followed by an oily product, (108 mg, 0.17 mmol, 17% yield). R_(f)=0.36 (18:1 CHCl₃ -EtOH). [α]_(D) =+5.8° (c=0.5, CHCl₃). [α]_(D) =+53.2°(c=0.73 MeOH). MS(CI) m/e 631(m+H).sup. +, 518, 458, 446, 368. ¹ HNMR(CDCl₃,300 MHz) δ 0.88-0.94(m,6H), 1.22-1.41(m,10H), 1.50-1.59(m,2H),2.96-3.30(m,5H), 3.52-3.62 (m,1H), 5.33-5.42(m,1H), 7.22(d,J=8 Hz,1H),7.30(d,J=8 Hz,1H), 7.37 (d,J=8 Hz,2H), 7.63(dt,J=1,7 Hz,1H),7.68(dt,J=1,7 Hz,1H), 7.79-7.93 (m,3H), 8.0(dd,J=1,8 Hz,1H), 8.16(d,J=8Hz,1H), 8.22(d,J=8 Hz,1H), 8.56(d,J=2 Hz,1H), 9.02(d,J=2 Hz,1H),9.32(d,J=2 Hz,1H), 9.54(d, J=2 Hz,1H). C,H,N analysis calculated for C₃₉H₄₂ N₄ O₄, H₂ O: C 72.20, H 6.84, N 8.64; found: C 72.38, H 6.62, N8.50.

EXAMPLE 40 N-(2'-Indolylcarbonyl)-R-tyrosine-di-n-pentylamide

The product of example 39b (200 mg, 0.56 mmol), indole-2-carboxylic acid(97 mg, 0.6 mmol) and TEA (84 μL, 0.6 mmol) were dissolved in 5 mL CH₂Cl₂ and treated with EDCI (115 mg, 0.6 mmol) at room temperature. After3 days, the solvent was evaporated and the residue was extracted as inexample 39a. Column chromatography on silica gel eluted with 1% EtOH inCH₂ Cl₂ provided product. R_(f) =0.38 (18:1 CH₂ Cl₂ -EtOH). mp=124°-7°C. [α]_(D) =+21.4° (c=1.17, MeOH). MS(CI) m/e 464(m+H)⁺. ¹ HNMR(CDCl₃,300 MHz) δ 0.88(apparent q,J=8 Hz,6H), 1.15-1.56(m, 12H),2.46-3.22(m,5H), 3.48-3.54(m,1H), 5.23-5.32(m,1H), 6.12(s, 1 H),6.70(d,J=8 Hz,2H), 6.95(d,J=1 1Hz,1H), 7.05(d,J=8 Hz,2H), 7.13(dt, J=1,7Hz,1H), 7.18(d,J=8 Hz,1H), 7.27(dt,J=1,7 Hz,1H), 7.40(d,J=8 Hz,1H),7.64(d, J=8 Hz,1H), 9.22(s,1H). C,H,N analysis calculated for C₂₈ H₃₇ N₃O₃ : C 72.54, H 8.05, N 9.06; found: C 72.37, H 8.10, N 8.80.

EXAMPLE 41 N-(3',4'-Dichlorobenzoyl)-R-tyrosine-di-n-pentylamide

The product of example 39b (103 mg, 0.29 mmol) was dissolved in 5 mL CH₂Cl₂ and treated with 3,4-dichlorobenzoylchloride (126 mg, 0.6 mmol) andTEA (84 gL, 0.6 mmol) at room temperature. After 2 hours, additionalacid chloride (13 mg) and TEA (8 μL) were added and the reaction wasstirred overnight. The volatiles were evaporated and the residue, inEtOAc, was extracted with 0.1% citric acid, H₂ O; then dried over MgSO₄,filtered and concentrated in vacuo. The resulting diacylated productresidue was dissolved in 10 mL of 1:1 THF-MeOH and treated with 1 N NaOH(290 mL, 0.29 mmol). After 1 hour, tlc revealed complete reaction andthe solvent was evaporated in vacuo. The residue was dissolved in EtOAcand acidified with 0.1M citric acid. The EtOAc layer was then washeduntil neutral, dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was warmed with 80% aqueous EtOH and cooled overnight to providea solid, 64 mg, 0.13 mmol (45% yield). mp=148°-52° C. [α]_(D) =+15.6°(c=1.0, MeOH). MS(CI) m/e 493(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ0.88-0.92(m,6H), 1.2-1.6(m,12H), 2.93-3.22(m,5H), 3.50-3.60(m, 1H),5.21-5.28(m,1H), 6.29(s,1H), 6.68(d,J=8 Hz,2H), 7.02(d,J=8 Hz, 2H),7.15(d,J=8 Hz,1H), 7.47(d,J=8 Hz,1H), 7.59(dd,J=2,8 Hz,1H), 7.91 (d,J=2Hz,1H). C,H,N analysis calculated for C₂₆ H₃₄ Cl₂ N₃ : C 63.28, H 6.94,N 5.68; found: C 63.39, H 7.00, N 5.54.

EXAMPLE 42 N-(2'-Naphthoyl)-R-tyrosine-di-n-pentylamide

The product of example 39b (100 mg, 0.28 mmol) was acylated with2-naphthoic acid (52 mg, 0.30 mmol) in the presence of TEA (39 μL, 0.28mmol) and EDCI (57 mg, 0.30 mmol) in 5 mL CH₂ Cl₂. The reaction andextractive workup were performed as in example 41a to yield 120 mg, 0.25mmol (89%). mp=128°-133° C. [α]_(D) =+11.8° (c=0.68, MeOH). MS(CI) m/e475(m+H)⁺, 303, 290. ¹ H NMR(CD₃ OD,300 MHz) δ 0.88-0.93(m,6H),1.19-1.38(m,9H), 1.44-1.62(m,3H), 2.99(dd,J=7,13 Hz,1H),3.08-3.29(m,4H), 3.37-3.47(m,1H), 5.22(dd,J=7,9 Hz,1H), 6.72(d,J=8Hz,2H), 7.13(d,J=8 Hz, 2H), 7.53-7.62(m,2H), 7.84(dd,J=2,9 Hz,1H),7.90-7.99(m,3H), 8.37 (s,1H). C,H,N analysis calculated for C₃₀ H₃₈ N₂O₃ : C 75.91, H 8.07, N 5.90; found: C 75.57, H 7.97, N 5.83.

EXAMPLE 43N-(3'-Quinolylcarbonyl)-(O-benzyl)-R-tyrosine-di-n-pentylamide Step 43a.N-t-Butyloxycarbonyl-(O-benzyl)-R-tyrosine-di-n-pentylamide

N-t-Butyloxycarbonyl-(O-benzyl)-R-tyrosine (3.71 g, 10 mmol) was stirredwith di-n-pentylamine (5.1 mL, 25 mmol), HOBt (1.4 g, 10 mmol) and TEA(1.4 mL, 10 mmol) in 150 mL CH₂ Cl₂ at 4° C. and then BOPCl (2.6 g, 10mmol) was added. The reaction was allowed to reach room temperatureovernight. After one day, additional BOPCl (260 mg) and TEA (140 μL)were added. After 2 days, the volatiles were evaporated and the residue(in EtOAc) was extracted with 0.1 M H₃ PO₄, 0.1M Na₂ CO₃, H₂ O; thendried over MgSO₄, filtered and concentrated in vacuo. The residue waschromatographed on silica gel eluted with 2:1 hexanes-EtOAc to yield anoil, 1.3 g, 2.55 mmol (25%). [α]_(D) =+5.8° (c=1.5, MeOH). MS(CI) m/e511 (m+H)⁺, 456, 393. ¹ H NMR(CDCl₃,300 MHz) δ 0.84-0.93(m,6H),1.1-1.35(m, 12H), 1.41(s,9H), 2.81-3.04(m,5H), 3.36-3.46(m,1H),4.15-4.23(m,1H), 5.03(s,2H), 5.32(d,J=8 Hz,1H), 6.87(d,J=8 Hz,2H),7.11(d,J=8 Hz,2H), 7.32-7.43(m,5H).

Step 43b. (O-Benzy)-R-tyrosine-di-n-pentylamide hydrochloride

The product of example 43a (1.3 g, 2.55 mmol) was treated with 5 mL of 4N HCl in dioxane, precooled to 4° C. The reaction mixture was thenallowed to reach room temperature. After 1 hour tlc revealed completereaction and the excess reagent was evaporate. The residue was placedunder high vacuum overnight to yield an oil, 1.2 g. R_(f) =0.59 (80:20:1CHCl₃ -MeOH-ammonium hydroxide). [α]_(D) =-32.5° (c=2.2, MeOH). MS(CI)m/e 411(m+H)⁺. ¹ H NMR(DMSO_(d6),300 MHz) δ 0.85(apparent q,J=7 Hz,6H),1.07-1.38(m,12H), 2.68-2.97(m,4H), 3.05(dd, J=5,13 Hz,1H), 3.32-3.42(m,2H), 4.27(dd,J=5,8 Hz,1H), 5.09(s,2H), 6.93(d,J=8 Hz,2H), 7.12(d, J=8Hz,2H), 7.32-7.43 (m,5H), 8.37(s,3H).

Step 43c. N-(3'-Quinolylcarbonyl )-(O-benzyl)-R-tyrosine-di-n-pentylamide

EDCI (290 mg, 1.5 mmol) was added to a cooled (4° C.) solution ofquinoline-3-carboxylic acid (260 mg, 1.5 mmol), the product of example43b (650 mg, 1.35 mmol), and TEA (418 μL, 3.0 mmol) in 5 mL CH₂ Cl₂. Thestirred reaction mixture was allowed to warm to room temperatureovernight. After evaporation of the volatiles, the residue was dissolvedin EtOAc and extracted with 0.1M H₃ PO₄ (3×), 0.1M Na₂ CO₃ (3×), brine(3×); then dried over MgSO₄, filtered and concentrated in vacuo to yieldan oil, 650 mg, 1.15 mmol (85%). R_(f) =0.77 (18:1 CHCl₃ -EtOH), 0.40(1:1 hexanes-EtOAc). [α]_(D) =+0.21° (c=0.47, CHCl₃). MS(FAB) m/e566(m+H)⁺, 393, 381. ¹ H NMR(CDCl₃,300 MHz) δ 0.91(apparent q,J=7Hz,6H), 1.17-1.38(m,10H), 1.43-1.6(m,2H), 2.86-3.17(m,5H), 3.49-3.59(m,1H), 5.03(s,2H), 5.26-5.33(m,1H), 6.90(d,J=8 Hz,2H), 7.16(d,J=8 Hz, 2H),7.28-7.43(m,6H), 7.62(dt,J=1,7 Hz,1H), 7.82(dt,J=1,8 Hz,1H), 7.90(d,J=8Hz,1H), 8.18(d,J=8 Hz,1H), 8.54(d,J=2 Hz,1H), 9.32(d, J=2 Hz,1H). C,H,Nanalysis calculated for C₃₆ H₄₃ N₃ O₃ : C 76.55, H 7.88, N 7.29; found:C 76.43, H 7.66, N 7.43.

EXAMPLE 44 N-(3'-Quinolylcarbonyl)-R-tyrosine-di-n-pentylamide

The product of example 43c (614 mg, 1.09 mmol) was dissolved in 30 mLMeOH and treated with 10% Pd/C (200 mg, pre-wetted with solvent undernitrogen) under 1 atmosphere hydrogen gas. Another 200 mg of catalystwas added after 4 hours and the reaction mixture was stirred overnight.The mixture was then filtered and the filtrate concentrated in vacuo.Silica gel column chromatography of the residue (eluted with a 2:1 to1:1 hexane-EtOAc step gradient) provided 270 mg, 0.57 mmol (52% yield).mp=135°-37° C. [α]_(D) =+12.6° (c=0.5, MeOH). MS(CI) m/e 476(m+H)⁺, 347,321,291. ¹ H NMR(CDCl₃,300 MHz) δ 0.91(t, J=7 Hz,6H), 1.24-1.38(m,8H),1.48-1.62(m,4H), 3.0-3.28 (m,5H), 3.51-3.61(m,1H), 5.30-5.38(m,1H),6.72(d,J=8 Hz,2H), 6.78(s,1H), 7.06(d,J=8 Hz,2H), 7.38(d,J=8 Hz,1H),7.60(t,J=7 Hz,1H), 7.80(dt, J=1,7 Hz,1H), 7.88(d,J=8 Hz,1H), 8.15(d,J=9Hz,1H), 8.58(d, J=2 Hz,1H), 9.27(d,J=2 Hz,1H). C,H,N analysis calculatedfor C₂₉ H₃₇ N₃ O₃ : C 73.23, H 7.84, N 8.83; found: C 73.23, H 7.89, N8.76.

EXAMPLE 45 N-(3'-Quinolylcarbonyl)-(O-bisulfatyl)-R-tyrosinedi-n-pentylamide ammonium salt

The product of example 44 (59 mg, 0.12 mmol) was dissolved in 2 mL DMFand treated with freshly prepared pyridine-sulfur trioxide complex (H.C. Reitz et al J. Amer. Chem. Soc. 68, 1031-5, 1946) overnight at roomtemperature. The pyridine was evaporated in vacuo and the DMF solutionwas poured into water and the pH adjusted to 7 with 1 N NaOH. Thehomogeneous solution was then frozen and lyophilized. Preparative C-18chromatography of the residue eluted with a gradient from 100% aqueousbuffer (0.05M ammonium acetate, pH 6.2) to 50% acetonitrile/aqueousbuffer over 10 minutes provided product fractions which were pooled,frozen and lyophilized to yield 48 mg, 0.08 mmol (67%). mp=113°-6° C.[α]_(D) =+12.2° (c=0.88, MeOH). MS(FAB) m/e 554(m-H)⁺, 368, 302, 298. ¹H NMR(D₂ O, 300 MHz) δ 0.68-0.75(m,6H), 0.98-1.43(m,12H),2.98-3.28(m,6H), 5.22(t,J=7 Hz,1H), 7.24(d,J=8 Hz,2H), 7.30(d,J=8Hz,2H), 7.44(t,J=8 Hz, 1H), 7.62(d,J=8 Hz,1H), 7.69(t,J=8 Hz,1H),7.82(d,J=8 Hz, 1H), 8.36(s, 1H), 8.78(s,1H). C,H,N analysis calculatedfor C₂₉ H₄₀ N₄ O₆ S, 0.50 H₂ O: C 59.88, H 7.10, N 9.63; found: C 59.77,H 6.82, N 9.11.

EXAMPLE 46 3,5-Di-iodo-N-(3'-quinolylcarbonyl)-R-Tyr-di-n-pentylamideand 3-Iodo-N-(3'-quinolylcarbonyl)-R-Tyr-di-n-pentylamide Example 46a.3.5-Di-iodo-N-(3'-quinolylcarbonyl)-R-Tyr-di-npentylamide

Iodine (27 mg, 0.11 mmol) was mixed with morpholine (40 μL, 0.46 mmol)in 5 mL MeOH and added to the product of example 46 (50 mg, 0.11 mmol)in 15 mL MeOH at room temperature. The reaction was stirred until tlcindicated complete reaction. After evaporation of the solvent,chromatography of the residue on silica gel eluted with a step gradientof CHCl₃ to 1% EtOH in CHCl₃ provided first the diiodo product followedby the monoiodo compound. Diiodo product (a): [α]_(D) =+18° (c=0.11,MeOH). MS(CI) m/e 728(m+H)⁺, 602. ¹ H NMR(CDCl₃,300 MHz) δ 0.92(apparent q,J=7 Hz,6H), 1.2-1.45(m,12H), 2.92-3.13(m,5H),3.53-3.67(m,1H), 5.22-5.28(m,1H), 5.72(s,1H), 7.27(d,J=7 Hz,1H), 7.56(s,2H), 7.63 (dt,J=1,8 Hz,1H), 7.83(dt,J=18 Hz,1H), 7.93(d,J=8 Hz,1H),8.18(d,J=1,8 Hz,1H), 8.55(d,J=2 Hz,1H), 9.33(d,J=2 Hz,1H). C,H,Nanalysis calculated for C₂₉ H₃₅ I₂ N₃ O₃, 0.4 EtOAc: C 48.19, H 5.05, N5.51; found: C 48.43, H 5.03, N 5.79.

Example 46b. 3-Iodo-N-(3'-quinolylcarbonyl)-R-Tyr-di-n-pentylamide

Monoiodo product (b): mp=75°-85° C. MS(CI) m/e 602(m+H)⁺. ¹ HNMR(CDCl₃,500 MHz) δ 0.84(apparent q,J=7 Hz,6H), 1.13-1.35 (m,9H),1.37-1.53(m,3H), 2.90-2.98(m,3H), 3.02-3.08(m,2H), 3.48-3.55(m,1H),5.18-5.23(m,1H), 6.83(d,J=8 Hz,1H), 7.05(dd,J=1,8 Hz, 1H), 7.22(d,J=8Hz,1H), 7.46(d,J=2 Hz,1H), 7.57(dt,J=1,8 Hz,1H), 7.76 (dt,J=1,8 Hz,1H),7.84(d,J=8 Hz,1H), 8.10(d,J=8 Hz,1H), 8.48(d,J=2 Hz, 1H), 9.24(d,J=2Hz,1H). C,H,N analysis calculated for C₂₉ H₃₆ IN₃ O₃, 1.5 H₂ O: C 55.42,H 6.25, N 6.69; found: C 55.19, H 5.95, N 6.17.

EXAMPLE 47N-(3'-Quinolylcarbonyl)-(O-methyl)-R-tyrosine-di-n-pentylamide

The product of example 44 (25 mg, 0.053 mmol) was dissolved in 1 mLacetone and K₂ CO₃ (8 mg, 0.058 mmol) and methyl iodide (5 μL 0.08 mmol)were added. After 3 hours at reflux, additional methyl iodide (5 mL) andacetone (2 mL) were added. After 2 days, the volatiles were evaporatedand the residue, in EtOAc, was extracted with 0.1% aqueous citric acid,water; then dried over MgSO₄, filtered and concentrated in vacuo. MS(CI)m/e 490(m+H)⁺, 476, 361,347, 317. ¹ H NMR(CDCl₃,300 MHz) δ0.86-0.93(m,6H), 1.2-1.56(m,12H), 2.42-3.15(m,5H), 3.49-3.59(m,1H),3.78(s,3H), 5.27-5.34(m,1H), 6.77(d,J=8 Hz,1H), 6.82(d,J=8 Hz,1H),7.08(d,J=8 Hz,1H), 7.16(d,J=8 Hz, 1H), 7.41-7.46(m,1H), 7.56-7.63(m,1H), 7.76-7.82(m,1H), 7.83-7.88(m,1H), 8.14(d,J=8 Hz,1H), 8.53(d,J=2Hz, 1H), 9.29(t,J=2 Hz,1H).

EXAMPLE 48 MethylN-(3'-quinolylcarbonyl)-(O-benzyl)-R-tyrosyl-S-phenylglycinate Step 48a.Methyl N-t-Butyloxycarbonyl-(O-benzyl)-R-tyrosyl-S-phenylglycinate

N-t-Butyloxycarbonyl-(O-benzyl)-R-tyrosine (1.0 g, 2.7 mmol), methylS-phenylglycinate hydrochloride (540 mg, 2.7 mmol), HOBt (362 mg, 2.7mmol) and TEA (374 μL, 2.7 mmol) were dissolved in 20 mL THF and treatedwith BOPCl (682 mg, 2.7 mmol). The reaction was followed by tlc (18:1CHCl₃ -EtOH) and additional BOPCl (200 mg) and TEA (374 μL) were addedafter 1,2 and 4 days. CH₂ Cl₂ (20 mL) also was added after 2 days. After1 week, the volatiles were evaporated in vacuo and the residue, inEtOAc, was extracted as in example 39a. Chromatography of the residue onsilica gel eluted with a step gradient from 9:1 to 2:1 hexanes-EtOAcyielded 485 mg, 1.13 mmol (42%). mp=138°-39° C. [α]_(D) =+48.7° (c=l.0,MeOH). MS(CI) m/e 519(m+H)⁺, 463,419. ¹ H NMR(CDCl₃,300 MHz) δ1.41(s,9H), 2.92-3.04(m,2H), 3.71(s,3H), 4.35(bs,1H), 5.01(s,3H),5.43-5.46(m,1H), 6.78(d,J=7 Hz, 1H), 6.82(d,J=8 Hz,2H), 7.02(d,J=8Hz,2H), 7.19-7.23(m,1H), 7.30-7.45(m,10H).

Step 48b. Methyl (O-Benzyl)-R-tyrosyl-S-phenylglycinate hydrochloride

The product of example 48a (450 mg, 1.05 mmol) was dissolved in 4 N HClin dioxane (5 mL, 20 mmol) precooled to 4° C. After 1 hour, the excessreagent was evaporated in vacuo and the product used directly in thenext step. mp=163°-6° C. [α]_(D) =+43.7° (c=0.76, MeOH). MS(FAB) m/e419(m+H)⁺, 403,226. ¹ H NMR(DMSO_(d6),300 MHz) δ 2.86-3.00(m,2H),3.67(s,3H), 4.13(bt, J=5 Hz,1H), 5.03(s,2H), 5.45(d,J=7 Hz,1H),6.88(d,J=8 Hz,2H), 7.05(d, J=8 Hz,2H), 7.22-7.25(m,2H), 7.33-7.46(m,8H),8.28(s,3H), 9.35(d, J=7 Hz,1H).

Step 48c. MethylN-(3'-quinolylcarbonyl)-(O-benzyl)-R-tyrosyl-S-phenylglycinate

Quinoline-3-carboxylic acid (182 mg, 1.05 mmol), TEA (146 μL, 1.05 mmol)and the product of example 48b (1.05 mmol) were dissolved in 20 mL CH₂Cl₂ and EDCI (201 mg, 1.05 mmol) was added at ambient temperature. After4 days, the volatiles were evaporated and the residue was extracted asin example 39a. The solvents were evaporated in vacuo to provide 407 mg,0.71 mmol (68% yield). top=153°-8° C. [α]_(D) =+73.0° (c=1.2, CHCl₃-MeOH/l:l). MS(FAB) m/e 574(m+H)⁺ 419, 381. ¹ H NMR(CDCl₃, 300 MHz) δ3.06(dd,l=8,14 Hz,1H), 3.20(dd,J=5,14 Hz,1H), 3.70(s, 3H),4.94-5.02(m,3H), 5.53(d,J=7 Hz,1H), 6.78(d,J=8 Hz, 2H), 6.83(d, J=7Hz,1H), 7.01(d,J=8 Hz,2H), 7.14(d,J=7 Hz,1H), 7.20-7.23(m,2H),7.33-7.36(m,4H), 7.39-7.44(m,4H), 7.62(dt,J=1,7 Hz, 1H), 7.82(dt, J=1,7Hz,1H), 7.88(d,J=8 Hz,1H), 8.15(d,J=8 Hz,1H), 8.54(d,J=2 Hz,1H),9.28(d,J=2 Hz,1H). C,H,N analysis calculated for C₃₅ H₃₁ N₃ O₅, 0.5 H₂O: C 72.15, H 5.54, N 7.21; found: C 72.05, H 5.63, N 6.88.

EXAMPLE 49 Methyl N-(3'-quinolylcarbony)-R-tyrosy-S-phenylglycinate

The product of example 48c (200 mg, 0.35 mmol) was dissolved in 10 mLCH₂ Cl₂ and treated with trimethylsilyliodide (TMSI, 198 μL, 1.39 mmol)at room temperature. Additional TMSI (198 μL) was added after 1 day.After 3 days, the reaction was quenched with MeOH for 5 minutes and thenpoured into 0.1M citric acid and extracted with EtOAc (3×). The combinedEtOAc solution was washed with water; then dried over MgSO₄, filteredand concentrated in vacuo. The crude solid was purified bychromatography on silica gel eluted with a step gradient of 1 to 5% EtOHin CH₂ Cl₂ and then crystallized from EtOAc and hexane to yield 51 mg(30%). mp=238°-40° C. [α]_(D) =+72.6° (c=0.23, MeOH). MS(CI) m/e484(m+H)⁺, 319. ¹ H NMR(CDCl₃ -CD₃ OD,300 MHz) δ3.0-3.16(m,2H),3.72(s,3H), 4.92-5.01(m,1H), 5.50(d,J=7 Hz,1H), 6.67(d,J=8 Hz,2H),6.99(d,J=8 Hz,2H), 7.21-7.24(m,2H), 7.35-7.38(m,3H), 7.40(s,1H),7.68(dt,J=1,7 Hz, 1H), 7.86(dt,J=1,7 Hz,1H), 7.98(d,J=8 Hz,1H),8.12(d,J=8 Hz,1H), 8.14(d,J=6 Hz,1H), 8.22(d, J=8 Hz,1H), 8.68(d,J=2Hz,1H), 9.21(d, J=2 Hz,1H). C,H,N analysis calculated for C₂₈ H₂₅ N₃ O₅: C 69.55, H 5.21, N 8.69; found: C 69.20, H 5.29, N 8.60.

EXAMPLE 50 N-(2'-Quinolylcarbonyl)-homoserine-di-n-pentylamide Step 50a.N'-Benzyloxycarbonyl-(2,R)-aminobutyrolactone

N-Benzyloxycarbonyl-R-methionine (283 mg, 1.0 mmol) and α-iodo acetamide(555 mg, 3.0 mmol) were dissolved in 6 mL of 50% aqueous EtOH and warmedto 4° C. for 4 days. Citric acid was added (3 mL of a 0.1M solution) andthe mixture was refluxed for 4 hours. After evaporation of thevolatiles, the residue was poured into water and extracted with EtOAc(3×). The combined EtOAc solution was extracted with 0.5 N HCl, water;then dried and concentrated vacuo. The resulting residue waschromatographed on silica gel eluted with 1:1 hexanes-EtOAc to yield 106mg, 0.52 mmol (52%). (cf: Ozinskas, A. J., Rosenthal, G. A., J. OrganicChem. 51, 5047, 1986). mp=124°-5° C. [α]_(D) =+31.3° (c=1.2, MeOH). ¹ HNMR(CDCl₃, 300 MHz) δ 2.16-2.28 (m,1H), 2.76-2.86(m,1H), 4.2-4.31(m,1H),4.37-4.50(m,2H), 5.13(s,2H), 5.32(bs,1H), 7.32-7.38(m,5H).

Step 50b. N-Benzyloxycarbonyl-homoserine-di-n-pentylamide

The product of example 50a (620 mg, 2.8 mmol) and dipentylamine (1.4 mL,7 mmol) were dissolved in 60 mL acetonitrile and then heated to refluxovernight. After evaporation of the volatiles, the residue waschromatographed on silica gel eluted with a step gradient from CHCl₃ to1% EtOH in CHCl₃ to yield an oil, 580 mg, 1.6 mmol (56%). [α]_(D)=+0.31° (c=0.96, MeOH). MS(CI) m/e 393(m+H)⁺, 253, 236, 192. ¹ HNMR(CDCl₃,300 MHz) δ 0.87-0.93(m,6H), 1.22-1.38 (m,8H), 1.47-1.63(m,4H),1.86-1.97(m,1H), 3.01-3.20(m,2H), 3.34-3.43(m,2H), 3.52-3.72(m,4H),4.76(dt,J=3,11 Hz,1H), 5.1(d,J=12 Hz, 1H), 5.13(d, J=12 Hz,1H),5.93(d,J=8 Hz,1H), 7.31-7.38(m,5H).

Step 50c. N-(2'-Quinolylcarbonyl)-homoserine-di-n-pentylamide

The product of example 50b is subjected to deprotection conditions as inexample 44 and then subsequently coupled with 2-quinoline carboxylicacid in a manner as in example 1.

EXAMPLE 51 N-(2'-Indolylcarbonyl)-R,S-homoserine-di-n-pentylamide Step51a. N'-(2'-Indolylcarbonyl)-(2,RS)-aminobutyrolactone

EDCI (191 mg, 1.0 mmol) was added to a solution of indole-2-carboxylicacid (161 mg, 1.0 mmol), α-aminobutyrolactone hydrobromide (182 mg, 1.0mmol), HOBt (135 mg, 1.0 mmol), and TEA (279 μL, 2.0 mmol) in 15 mL CH₂Cl₂ at room temperature. Additional EDCI (120 mg) and TEA (56 μL) wereadded after 1 day. After 5 days, the volatiles were evaporated and theresidue, in EtOAc, was extracted with 1M H₃ PO₄, 0.1M Na₂ CO₃, andbrine. The solution was dried over MgSO₄, filtered and concentrated invacuo. The product was crystallized from EtOAc to yield 147 mg, 0.6mmol, 60%. R_(f) =0.17 (1:1 hexanes-EtOAc). mp=235°-6° C. MS(CI) m/e245(m+H)⁺ 144. ¹ H NMR(CDCl₃ -CD₃ OD,300 MHz) δ 1.86-2.51(m,1H),2.19-2.79(m,1H), 4.32-4.42 (m,1H), 4.56(dt,J=2,11 Hz,1H), 4.82(dd,J=8,11Hz,1H), 7.1-7.15(m, 2H), 7.28(dt, J=1,8 Hz,1H), 7.40(s,0.5 H),7.46(d,J=8 Hz,1H), 7.66(d, J=8 Hz,1H).

Step 51 b. N-(2'-Indolylcarbonyl)-R,S-homoserine-di-n-pentylamide

The product of example 51a (25 mg, 0.1 mmol) and dipentylamine (50 μL,0.25 mmol) were dissolved in 2 mL THF and warmed to 50° C. Additionaldipentylamine (250 μL) was added after several hours. After 4 days, thevolatiles were evaporated and the residue was chromatographed on silicaeluted with 2:1 hexanes-EtOAc. Yield: 26 mg, 0.06 mmol, 60%.mp=128°-139° C. MS(CI) m/e 402(m+H)⁺, 158. ¹ H NMR(CDCl₃, 300 MHz) δ0.92(t,J=7 Hz,6H), 1.26-1.42(m,10H), 1.52-1.72(m,3H), 1.98-2.11(m,1H),2.69(t,J=8 Hz,1H), 3.06-3.26(m,2H), 3.42-3.52(m, 1H), 3.60-3.77(m,3H),5.12-5.20(m,1H), 7.03(d,J=1Hz,1H), 7.16(dt, J=1,8 Hz,1H), 7.31(dt,J= 1,7Hz,1H), 7.42(dd,J=1,8 Hz,1H), 7.48(d, J=8 Hz,1H), 7.67(d,J=8 Hz,1H),9.13(s,1H). C,H,N analysis calculated for C₂₃ H₃₅ N₃ O₃, 0.5 H₂ O: C67.28, H 8.84, N 10.24; found: C 67.42, H 8.64, N 10.10.

EXAMPLE 52 N-(3'-Quinolylcarbonyl)-R,S-homoserine-di-n-pentylamide Step52a. N'-(3'-Quinolylcarbonyl)-(2,RS)-aminobutyrolactone

Quinoline-3-carboxylic acid (5.2 g, 30 mmol) was coupled toα-aminobutyrolactone (5.5 g, 30 mmol) in a manner similar to that inexample 51a to provide 2.62 g, 10.2 mmol (34% yield). Additionalextraction of the aqueous layer with EtOAc yielded another 820 mg, 3.2mmol (10.7%). R_(f) =0.26 (18:1 CHCl₃ -EtOH). mp=160°-63° C. MS(CI) m/e257(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 2.32-2.46(m,1H), 2.91-3.01(m,1H),4.35-4.43(m,1H), 4.56(dt, J=2,10 Hz,1H), 4.83-4.92(m,1H), 7.36(d,J=6Hz,1H), 7.60(dt,J=1,8 Hz, 1H), 7.81(dt,J=2,8 Hz,1H), 7.86(d,J=8 Hz,1H),8.12(dd,J=1,8 Hz,1H), 8.59(dd,J=1,2 Hz,1H), 9.28(d,J=2 Hz,1H). C,H,Nanalysis calculated for C₁₄ H₁₂ N₃ : C 65.61, H 4.72, N 10.93; found: C65.42, H 4.82, N 10.82.

Step 52b. N-(3'-Quinolylcarbonyl)-R,S-homoserine-di-n-pentylamide

The product of example 52a (500 mg, 2.0 mmol) was treated withdipentylamine (1.5 mL, 7.4 mmol) in 25 mL of toluene and refluxed. After2 days, an additional 1 mL of dipentylamine was added and the heatingwas continued. After 1 week, the volatiles were evaporated in vacuo andthe excess amine was removed by Kugelrohr distillation. The residue wasthen chromatographed on silica gel eluted with a step gradient of CHCl₃to 4% EtOH in CHCl₃ to yield an oil, 611 mg, 1.48 mmol (74%). MS(CI) m/e414(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 0.88-0.95(m,6H), 1.25-1.42(m,7H),1.52-1.75(m,5H), 2.04-2.15(m,1H), 3.06-3.28(m,2H), 3.46-3.57(m, 2H),3.62-3.81(m,3H), 4.01(dd,J=5,9 Hz,1H), 5.21-5.28(m,1H), 7.63 (dt,J= 1,8Hz,1H), 7.72(d,J=7 Hz,1H), 7.83(dt,J=1,8 Hz,1H), 7.93(dd, J=1,7 Hz,1H),8.18(d,J=8 Hz,1H), 8.62(d,J=2 Hz,1H), 9.37(d,J=3 Hz,1H). C,H,N analysiscalculated for C₂₄ H₃₅ N₃ O₃, 0.25 H₂ O: C 68.95, H 8.56, N 10.05;found: C 69.26, H 8.45, N 10.06.

EXAMPLE 53 N-(3'-Quinolylcarbonyl)-R,S-homoserine-n-pentylamide

The product of example 52a (200 mg, 0.8 mmol) and n-pentylamine (232 μL,2.0 mmol) were dissolved in 20 mL of 1:1 THF-acetonitrile and stirred atroom temperature until starting material was consumed (tlc: R_(f) =0.15,18:1 CHCl₃ -EtOH). The volatiles were evaporated in vacuo. The residuewas mixed with hexanes and the product filtered away to yield 273 mg,0.79 mmol (99%). mp=181°-3° C. MS(CI) m/e 344(m+H)⁺. ¹ H NMR (CDCl₃,300MHz) δ 0.91(t,J=7 Hz,3H), 1.30-1.38(m,4H), 1.51-1.58(m, 2H),1.95-2.04(m,1H), 2.12-2.21(m,1H), 3.25-3.36(m,2H), 3.80(bs, 2H),4.26(bs,1H), 4.83-4.90(m,1H), 7.37(bt,J=3 Hz,1H), 7.64(dt, J=1,5 Hz,1H),7.83(dt,J=1,6 Hz,1H), 7.93(d,J=6 Hz,1H), 8.10(d,J=6 Hz, 1H), 8.15(d,J=7Hz,1H), 8.68(d,J=2 Hz,1 H), 9.37(d,J=1 Hz,1H). C,H,N analysis calculatedfor C₁₉ H₂₅ N3O₃, 0.25 CHCl_(3:) C 61.13, H 6.82, N 11.26; found: C60.82, H 6.88, N 11.16.

EXAMPLE 54 N-(3'-Quinolylcarbonyl)-R-methionine-di-n-pentylamide Step54a. N-t-Butyloxycarbonyl-R-methionine-di-n-pentylamide

BOPCl (5.1 g, 20 mmol) was added to a cooled solution (4° C.) ofN-t-Butyloxycarbonyl-R-methionine (5.0 g, 20 mmol), dipentylamine (8.0mL, 40 mmol), in 60 mL of dry THF and the stirred reaction was allowedto attain room temperature overnight. The volatiles were evaporated invacuo. The residue was dissolved in EtOAc and extracted successivelywith 1M H₃ PO₄ (3×), 1M Na₂ CO₃ (3×), brine (3×); then dried over MgSO₄,filtered and concentrated in vacuo to yield an oil: 4.6 g, 11.7 mmol(59%). R_(f) =0.81 (1:1 hexanes-EtOAc). [α]_(D) =+27.5° (c=2.7, MeOH).MS(CI) m/e 389(m+H)⁺, 333, 311, 258, 219, 202, 158. ¹ H NMR(CDCl₃,300MHz) δ 0.86-0.93(m,6H), 1.21-1.37(m,9H), 1.42(s, 9H), 1.43-1.66 (m,3H),1.76-1.96(m,2H), 2.11(s,3H), 2.54(t,J=7 Hz, 2H), 3.06-3.15(m,1H),3.19-3.29(m,1H), 3.32-3.42(m,1H), 3.46-3.56(m,1H), 4.68-4.75(m,1H),5.37(d,J=9 Hz,1H).

Step 54b. R-Methionine-di-n-pentylamide trifluoroacetate salt

The product of example 54a (4 g, 10.3 mmol) was dissolved in 30 mL TFAprecooled to 4° C. After 2 hours, the excess reagent was evaporated andthe residue was placed under high vacuum overnight. [α]_(D) =+5.1°(c=1.4, MeOH). MS(CI) m/e 289(m+H)⁺. ¹ H NMR(DMSO_(d6),300 MHz) δ0.88(apparent q,J=8 Hz,6H), 1.18-1.35 (m,8H), 1.42-1.58(m,4H),1.89-1.96(bm,2H), 2.08(s,3H), 2.43-2.67 (m,2H), 3.00-3.09(m,1H),3.13-3.23(m,1H), 3.28-3.38(m,1H), 3.48-3.57(m,1H), 4.2-4.28(m,1H),8.17(s,3H).

Step 54c. N-(3'-Quinolylcarbonyl)-R-methionine-di-n-pentylamide

Quinoline-3-carboxylic acid (0.43 g, 2.5 mmol), the product of example54b (1.0 g, 2.5 mmol), and TEA (697 μL, 5 mmol) were dissolved in 15 mLof CH₂ Cl₂ cooled to 4° C. and EDCI (0.48 mg, 2.5 mmol) was added. Thestirred reaction mixture was allowed to attain room temperatureovernight. The volatiles were evaporated and the residue in EtOAc wasextracted with 0.1M citric acid, 0.1M Na₂ CO₃, water; then dried overMgSO₄, filtered and concentrated in vacuo. Silica gel chromatography ofthe residue eluted with a step gradient of CHCl₃ to 0.5% EtOH in CHCl₃yielded an oil, 572 mg, 1.29 mmol (52%). R_(f) =0.19 (1:1hexanes-EtOAc). [α]_(D) =+8.0° (c=0.85, MeOH). MS(CI) m/e 444(m+H)⁺. ¹ HNMR(CDCl₃,300 MHz) δ 0.91(t,J=7 Hz, 3H), 0.93(t,J=7 Hz,3H),1.23-1.42(m,8H), 1.52-1.62(m,2H), 1.63-1.75(m,2H), 2.02-2.17(m,5H),2.56-2.72(m,2H), 3.10(t,J=8 Hz,0.5H), 3.14(t,J=8 Hz,0.5H),3.25-3.35(m,1H), 3.46-3.55(m,1H), 3.59(t,J=8 Hz,0.5H), 3.63(t,J=8 Hz,0.5H), 5.28-5.36(m,1H), 7.55(d,J=8 Hz, 1H), 7.12(dt,J=1,7 Hz,1H),7.81(dt,J=1,8 Hz,1H), 7.88(dd,J=1,8 Hz,1H), 8.15(d,J=8 Hz,1H), 8.54(d,J=2 Hz,1H), 9.33(d,J=2 Hz,1H). C,H,N analysis calculated for C₂₅ H₃₇ N₃O₂ S, 0.5 H₂ O: C 66.33, H 8.46, N 9.28; found: C 66.33, H 8.19, N 9.25.

EXAMPLE 55N-(3'-Quinolylcarbonyl)-R-methioninesulfoxide-di-n-pentylamide

The product of example 54c (100 mg, 0.23 mmol) was dissolved in 5 mL THFand m-chloroperbenzoic acid (47 mg, 0.23 mmol) was added at roomtemperature. The reaction was stirred overnight. The volatiles wereevaporated and the residue, in EtOAc, was extracted with water until theaqueous extract was neutral (pH=7); then the solution was dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel eluted with CH₂ Cl₂ and EtOH to provide theproduct as an oil. [α]_(D) =8.8° (c=0.73, MeOH). MS(CI) m/e 460(m+H)⁺,396. ¹ H NMR(CDCl₃,300 MHz) δ 0.92(apparent q,J=7 Hz,6H),1.26-1.40(m,10H), 1.52-1.73(m,3H), 2.14-2.26(m,1H), 2.39-2.52(m,1H),2.71-3.02(m,3H), 3.08-3.18(m,1H), 3.23-3.35(m,1H), 3.38-3.52(m, 1H),3.58- 3.68(m,1H), 5.20-5.34(m,1H), 7.62(tt,J=1,8 Hz,2H), 7.72 (d,J=7Hz,1H), 7.83(tt,J=1,8 Hz,1H), 7.92(d,J=8 Hz,1H), 8.17(d,J=8 Hz, 1H),8.62(dd,J=2,5 Hz,1H), 9.35(dd,J=2,3 Hz,1H). C,H,N analysis calculatedfor C₂₅ H₃₇ N₃ O₃ S,0.1 EtOAc: C 65.13, H 8.13, N 8.97; found: C 65.31,H 8.30, N 8.73.

EXAMPLE 56N-(3'-Quinolylcarbonyl)-(O-methyl)-R,S-homoserine-di-pentylamide

The product of example 52b is methylated in a similar manner to that inexample 22 to provide the title compound after purification bychromatography.

EXAMPLE 57N-(3'-Quinolylcarbonyl)-(O-benzyl)-R,S-homoserine-di-n-pentylamide

The product of example 52b is benzylated in a manner similar to that inexample 22 utilizing benzyl bromide as the alkylating agent. The titlecompound was provided after purification by chromatography.

EXAMPLE 58 N-(2'-Indolylcarbonyl )-R-Proline-di-n-pentylamide Step 58a.N-t-Butyloxycarbony-R-Proline-di-n-pentylamide

BOPCl (1.18 g, 4.64 mmol) was added to a cooled solution (4° C.) ofN-t-Butyloxycarbonyl-R-Proline (1.0 g, 4.64 mmol), dipentylamine (2.5mL, 12.5 mmol), in 50 mL of dry THF. The cooling bath was removed andthe stirred reaction mixture was allowed to warm to ambient temperaturegradually. After 5 hours, the volatiles were evaporated in vacuo. Theresidue was dissolved in EtOAc and extracted successively with 1M H₃ PO₄(3×), 1M Na₂ CO₃ (3×), brine (3×); then dried over MgSO₄, filtered andconcentrated in vacuo to yield an oil, 880 mg, 2.48 mmol (54%). R_(f)=0.28 (2:1 hexanes-EtOAc). [α]_(D) =+28.7° (c=1.0, MeOH). MS(CI) m/e355m+H)⁺, 299, 255. ¹ H NMR(CDCl₃,300 MHz) δ 0.84-0.94(m,6H),1.23-1.38(m,8H), 1.41(s.,6H), 1.45(s,3H), 1.49-1.58(m,6H),1.80-1.90(m,1H), 2.0-2.23(m,1H), 3.12-3.33(m,4H), 3.4-3.52(m,1H),3.56-3.67(m,1H), 4.44(dd,J=4,8 Hz,0.6H), 4.58(dd,J=2,8 Hz,0.4H).

Step 58b, R-Proline-di-n-pentylamide hydrochloride

The product of example 58a (800 mg, 2.3 mmol) was mixed with HC₁-Dioxane (12.5 mL, 50 mmol, pre-cooled to 4° C.) under an N₂ atmosphereat ambient temperature. After 1 hour, the volatiles were evaporated invacuo and the residue was mixed with toluene and concentrated (twice)then placed under high vacuum overnight. The residue was utilizeddirectly.

Step 58c. N-(2'-Indolylcarbonyl)-R-Proline-di-n-pentylamide

EDCI (440 mg, 2.3 mmol) was added to a cooled (4° C.) solution ofindole-2-carboxylic acid (371 mg, 2.3 mmol), the product of example 58b(2.3 mmol assumed), HOBt (311 mg, 2.3 mmol), and TEA (321 μL, 2.3 mmol)in 10 mL CH₂ Cl₂. The stirred reaction was allowed to attain ambienttemperature overnight. The volatiles were evaporated and the residue wasdissolved in EtOAc and extracted with 1 M H₃ PO₄ (3×), 1M Na₂ CO₃ (3×),brine (3×); then dried over MgSO₄, filtered and concentrated to anorange oil. The crude product was purified by chromatography on silicaeluted with 2:1 hexanes-EtOAc to yield 0.92 g, 2.4 mmol (92%) as aslightly yellow glass. R_(f) =0.22 (2:1 hexanes-EtOAc). The glass wasdissolved in hot hexanes-EtOAc, then cooled slowly to -20 ° C. An oilseparated out and over 24 hours solidified. The solution was decantedand the solid was collected using hexanes to yield 769 mg (84%).mp=63°-7° C. [α]_(D) =-20.4° (c=1.0, MeOH). MS(CI) m/e 398(m+H)⁺, 241,213. ¹ H NMR(CDCl₃,300 MHz) δ 0.88(t, J=7 Hz,3H), 0.93(t,J=6 Hz,3H),1.24-1.43(m,8H), 1.51-1.75(m,3H), 1.80-1.90(m,1H), 1.94-2.28(m,3H),2.32-2.45(m,1H), 3.16-3.37(m, 2H), 3.43-3.54(m,2H), 4.0-4.08(m,1H),4,12-4.2(m,1H), 5.02(dd, J=4,8 Hz,1H), 6.96(bs,1H), 7.12(dt,J=l,8Hz,1H), 7.28(dt,J=l,7 Hz,1H), 7.48(dd,J=l,8 Hz,1H), 7.67(d,J=8 Hz,1H),9.30(s,1H) C,H,N analysis calculated for C₂₄ H₃₅ N₃ O₂ : C 72.50, H8.87, N 10.57; found: C 72.55, H 8.91, N 10.49.

EXAMPLE 59 N-(3'-Quinolylcarbonyl)-R-lysine-di-n-pentylamidehydrobromide

The product of example 35c (1.61 g, 2.64 mmol) was treated with 15 mL ofHBr in HOAc (1.1 N, 16.5 mmol) for 2 hours under an inert atmosphere.The solvent was evaporated and the residue was purified bychromatography on silica gel eluted with a CH₂ Cl₂ to 1% EtOH in CH₂ Cl₂step gradient to yield 1.25 g, 2.39 mmol (91%) as a yellow glass.mp=85°-95° C. ¹ H NMR(DMSO_(d6),300 MHz) δ 0.85(t,J=7 Hz,6H),1.23-1.83(m,18H), 2.78(t,J=7 Hz,2H), 3.06-3.17(m,1H), 3.28-3.44(m,3H),4.86-4.93(m,1H), 7.57(bs,2H), 7.72(dt,J=1,7 Hz,1H), 7.88(dt,J=1,7Hz,1H), 8.10(d,J=8 Hz,2H), 8.92(d, J=2 Hz,1H), 9.02(d,J=8 Hz,1H),9.32(d,J=2 Hz,1H).

EXAMPLE 60 N.sup.α -(3'-Quinolylcarbonyl)-N.sup.ε-phenylthiolcarbonyl-R-lysine dipentylamide

The product of example 59 (20 mg, 0.045 mmol) was treated withcarbonyldiimidazole (8.1 mg, 0.05 mmol) in 10 mL CH₂ Cl₂ at roomtemperature overnight. Thiophenol (10.3 μL, 0.10 mmol)and 10 mL THF wereadded and the mixture was heated to 60° C. After 1 day, the reaction waseluted on silica gel with 1% EtOH in CH₂ Cl₂ to yield an oil. MS(CI) m/e577(m+H)⁺, 467, 420. ¹ H NMR(CDCl₃,300 MHz) δ 0.88-0.96(m,6H),1.23-1.86(m,18H), 3.12 (dt,J=7,13 Hz,1H), 3.22-3.44(m,4H),3.59(dt,J=7,13 Hz,1H), 5.0-5.17 (m,1H), 5.70(t,J=5 Hz, 1H),7.32-7.37(m,3H), 7.47-7.51(m,3H), 7.62 (dt,J=1,8 Hz,1H), 7.82(dt,J=1,7Hz,1H), 7.91(dd,J=1,8 Hz,1H), 8.16(d, J=8 Hz,1H), 8.63(d,J=2 Hz,1H),9.37(s,J=2 Hz,1H).

EXAMPLE 61N-(3'-Quinolylcarbonyl)-R-phenylglycine-(2'-propylpiperidinyl)amide Step61a. N-Benzyloxycarbonyl-R-Phenylglycine-(2'-propylpiperidinyl)amide

N-Benzyloxycarbonyl-R-phenylglycine (1.0 g, 3.5 mmol),2-propylpiperidine (1 mL, 6.64 mmol), HOBt (475 mg, 3.5 mmol) and TEA(490 μL, 3.5 mmol) were dissolved in 25 mL of CH₂ Cl₂ and treated withBOPCl (890 mg, 3.5 mmol). Additional TEA (490 μL) and BOPCl(890 mg) wereadded after 2 days. After 6 days, the solvent was evaporated and thecrude reaction was purified by chromatography on silica gel eluted witha 9:1 to 4:1 hexane-EtOAc step gradient to yield 179 mg, 0.454 mmol(13%). mp=100°-115° C. [α]_(D) =-13.5° (c=1.0, MeOH). MS(CI) m/e395(m+H)⁺, 261. ¹ H NMR(CDCl₃,300 MHz) δ 0.52(t,J=7 Hz,1H), 0.92(t,J=7Hz,2H), 1.18-1.70(m,10H), 2.56-2.67(m,0.33H), 3.01(dd,J=2,13 Hz,0.67H),3.57(bd,J=12 Hz,0.67H), 3.80(bs,0.33H), 4.51(bd,J=13 Hz,0.33H),4.78(bs,0.67H), 4.98(d,J= 11 Hz,1H), 5.12(d,J= 11 Hz,1H), 5.54(d, J=7Hz,0.67H), 5.58(d,J=7 Hz,0.33H), 6.46-6.55(m,1H), 7.28-7.43 (m, 10H).

Step 61 b. R-Phenylglycine-(2'-propylpiperidinyl)amide

The product of example 61a (150 mg, 0.38 mmol) was treated with 25 mg of10% Pd on carbon in 5 mL of MeOH under one atmosphere of hydrogen for 24hours. The catalyst was filtered away and the filtrate was evaporated toyield product.

Step 61c.N-(3'-Quinolylcarbonyl)-R-phenylglycine-(2'-propylpiperidinyl)amide

Quinoline-3-carboxylic acid (38.1 mg, 0.22 mmol), the product of example61b (31 mg, 0.22 mmol) and TEA (31 μL, 0.22 mmol) were dissolved in 4 mLof 1:1 DMF-CH₂ Cl₂ and treated with EDCI (42.1 mg, 0.22 mmol) withstirring at room temperature overnight. The solvent was evaporated andthe residue was extracted as in example 39a. R_(f) =0.4 (1:1hexane-EtOAc). MS(CI) m/e 416(m+H)⁺, 261, 154, 128. ¹ H NMR(CDCl₃,300MHz) δ 0.55(t, J=7 Hz,1H), 0.94(t,J=7 Hz,2H), 1.23-1.72(m,10H),2.71(dt,J=2,13 Hz, 0.33H), 3.08(dt,J=2,13 Hz,0.67H), 3.68(bd,J=13 Hz,0.67H), 3.93(bs, 0.33H), 4.58(bd,J=13 Hz,0.33H), 4.85(bs,0.67H),6.03(d,J=7 Hz, 0.67H), 6.07(d,J=7 Hz,0.33H), 7.3-7.42(m,3H),7.52-7.63(m,3H), 7.80(dt,J=l,7 Hz,1H), 7.90(d,J=8 Hz,1H), 8.14(d,J=8Hz,1H), 8.28(t, J=6 Hz,1H), 8.59(d,J=2 Hz,1H), 9.34(d,J=2 Hz,1H). C,H,Nanalysis calculated for C₂₆ H₂₉ N₃ O₂,0.5 H₂ O: C 73.56, H 7.12, N 9.90;found: C 73.60, H 7.10, N 9.61.

EXAMPLE 62 N-(4',8 '-Dihydroxy-2'-quinolylcarbonyl)-R-phenylglycine-(2'-propylpiperidinyl)amide

4,8-Dihydroxyquinoline-2-carboxylic acid (45 mg, 0.22 mmol), the productof example 61b (52 mg, 0.20 mmol) and TEA (31 μL, 0.22 mmol) weredissolved in 4 mL of 1:1 DMF-CH₂ Cl₂ and treated with EDCI (42 mg, 0.22mmol) with stirring overnight. The reaction was then poured into EtOAcand extracted as in example 39a. The resulting residue was purified bychromatography on silica gel eluted with a 1% to 9% EtOH in CH₂ Cl₂ stepgradient. MS(CI) m/e 448(m+H)⁺, 293. ¹ H NMR (DMSO_(d6),300 MHz) δ0.71(t,J=7 Hz,1H), 0.81-0.90(m,2H), 1.15-1.70(m,10H), 3.07(bt,J=13Hz,0.67H), 3.33(s,H₂ O), 3.68(bd, J=12 Hz,0.67H), 4.02(bs,0.33H),4.36(d,J=8 Hz,0.33H), 4.68(bs, 0.67H), 6.12-6.17(m,1H), 7.09(d,J=7Hz,1H), 7.32-7.56(m,8H), 9.84(d,J=8 Hz,0.67H), 10.08(d,J=8 Hz,0.33H),10.23(s,0.67H), 10.24(s,0.33H), 11.73(bs,1H).

EXAMPLE 63N-(3'-Quinolylcarbonyl)-R-phenylglycine(N-benzyl,N-2'-cyanoethyl)amideStep 63a. N.sup.α-Benzyloxycarbonyl-R-phenylglycine-(N-benzyl,-N-2'-cyanoethyl)amide

N-Benzyloxycarbonyl-R-phenylglycine (285 mg, 1.0 mmol),3-(benzylamino)propionitrile (391 μL, 2.5 mmol) and TEA (139 μL, 1.0mmol) were dissolved in 10 mL of CH₂ Cl₂ and treated with BOPCl (256 mg,1.0 mmol). After 1 day, another 139 μL of TEA was added. After 2 days,additional BOPCl (256 mg), amine (391 μL) and DMF (5 mL) were added.After 3 days, the solvents were evaporated and the residue was extractedas in example 39a. The crude residue was recrystallized fromhexanes-EtOAc to yield 314 mg, 0.74 mmol (74%). R_(f) =0.75 (1:1hexanes-EtOAc). mp=114°-150° C. [α]_(D) =-9.4° (c=0.67, 1:1 DMF-MeOH).MS(CI) m/e 428(m+H)⁺, 445, 384, 375. ¹ H NMR(CDCl₃,300 MHz) δ 2.45-2.66(m,2H), 3.33-3.42(m,1H), 3.46-3.52(m,0.5H), 3.66-3.75(m,1H), 4.38(d,J=16Hz,1H), 4.43-4.5(m,0.5H), 4.63(d,J=16 Hz,1H), 4.69(s, 0.5H),5.01-5.2(m,3H), 5.59(d,J=7 Hz,0.5H), 5.66(d,J=7 Hz,1H), 6.88 (s,0.5H),6.18-6.27(m,1.5H), 6.82(bs,0.5H), 6.95(t,J=4 Hz,2H), 7.10-7.18(m,2H),7.28-7.39(m,15H). C,H,N calculated for C₂₆ H₂₅ N₃ O₃, 0.1 H₂ O: C 72.74,H 5.92, N 9.79; found: C 72.79, H 5.99, N 9.40.

Step 63b. R-Phenylglycine-(N-benzyl-N-2'-cyanoethyl)amide

The product of example 63a (225 mg, 0.53 mmol) was dissolved in 25 mL ofEtOH and treated with 100 mg of 10% Pd/C at room temperature. After 1.5hours, the catalyst was filtered and the filtrate was evaporated toyield 158 mg, 0.54 mmol(quantitative). MS(CI) m/e 294(m+H)⁺, 241.

Step 63c.N-(3'-Quinolylcarbonyl)-R-phenylglycine(N-benzyl,N-2'-cyanoethyl)amide

Quinoline-3-carboxylic acid (35 mg, 0.20 mmol) and the product ofexample 63b (53 mg, 0.18 mmol) were dissolved in 10 mL of CH₂ Cl₂ andtreated with EDCI (38 mg, 0.20 mmol). After 1 day, the solvent wasevaporated and the residue was extracted as in example 39a to give 54mg, 0.12 mmol (67%). [α]_(D) =-0.42° (c=2.6, CHCl₃). mp=57°-63° C.MS(CI)m/e 449(m+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ 1.90-2.02(m,0.25H),2.27-2.38(m,0.25H), 2.49-2.72(m,1.5H), 3.42(dt,J=7,13 Hz,1H),3.81(dt,J=7,13 Hz,1H), 4.46(d, J=16 Hz,1H), 4.73(d,J=16 Hz,1H),6.11(d,J=6 Hz,0.25H), 6.16(d,J=7 Hz, 0.75H), 6.98-7.02(m,2H),7.19-7.22(m,0.5H), 7.30-7.33(m,2.5H), 7.38-7.46(m,3H), 7.53-7.64(m,3H),7.82(dt,J=1,7Hz,1H), 7.85-7.94 (m,2H), 8.15(d,1H, J=8 Hz), 8.61(d,J=1Hz,1H), 9.33(d,J=1 Hz,1H). C,H,N analysis calculated for C₂₈ H₂₄ N₄ O₂,0.7 H₂ O: C 72.93, H 5.55, N 12.15; found: C 72.86, H 5.58, N 11.77.

EXAMPLE 64 N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-phenylglycine(N-benzyl,N-2'-cyanoethyl)amide

4,8-Dihydroxyquinoline-2-carboxylic acid (41 mg, 0.20 mmol), the productof example 65b (53 mg, 0.18 mmol), and TEA (28 μL, 0.20 mmol) weredissolved in 5 mL of DMF and treated with EDCI (38 mg, 0.20 mmol).Additional TEA (28 μL) and EDCI (38 mg) were added after 2 hours and 1day. After 2 days HOBt (27 mg, 0.20 mmol) was added to the reactionmixture. After 3 days, the solvent was evaporated and the residue wasextracted with 0.1 M citric acid, and water and the organic solution wasdried over MgSO₄ then filtered and concentrated. The crude product waspurified by silica get chromatography eluted with 1:1 hexanes-EtOAc toprovide 22.6 mg, 0.05 mmol (26%). R_(f) =0.4 (1:1 hexane-EtOAc).mp=218°-222° C. [α]_(D) =-4.8° (c= 0.42, MeOH). MS(CI) m/e 481(m+H)⁺,428. ¹ H NMR(CD₃ OD,300 MHz) δ 2.47-2.58(m,0.33H), 2.6-2.82(m,2H),3.33-3.62(m,2.33H), 3.68-3.78(m,0.33H), 3.82-3.91(m,1H), 4.53(d,J=16Hz,1H), 4.62(d, J=14 Hz,0.33H), 4.76(d, J=16 Hz,1H), 4.87(s,H₂ O),4.92(d,J=5 Hz, 0.33H), 6.18(s,1H), 7.10(dd, J=1,7 Hz,1H),7.2-7.35(m,7H), 7.39-7.46(m,3H), 7.51-7.60(m,2H), 7.67(dd,J=1,8 Hz,1H).

EXAMPLE 65 N-(3'-Quinolylcarbonyl)-R-tyrosine-di-n-pentylamidehydrochloride

The product of example 44 (1.5 g, 3.0 mmol) was treated with 1.4 N HClin dioxane (11 mL, 15 mmol) for 10 minutes. The excess reagent wasevaporated and the oily residue was triturated with diethylether andfiltered to yield 1.3 g, 2.6 mmol (87%) of a pale yellow solid. MS(CI)m/e 476(m+H)⁺, 458. ¹ H NMR(DMSO_(d6), 300 MHz) δ 0.84(t,J=7 Hz,6H),1.15-1.62(m,12H), 2.87-3.22(m,3H), 3.29-3.40(m,3H), 5.02(apparent q,J=7Hz,1H), 6.66(d,J=8 Hz,2H), 7.11(d,J=8 Hz,2H), 7.78(dt,J=1,8 Hz,1H),7.96(dt,J=1,8 Hz,1H), 8.17(t,J=7 Hz,2H), 9.04(d,J=2 Hz,1H), 9.22(d,J=8Hz,1H), 9.33(d, J=2 Hz,1H). C,H,N analysis calculated for C₂₉ H₃₇ N₃ O₃,1.3 HCl: C 66.60, H 7.38, N 8.03; found: C 66.43, H 7.38, N 7.99.

EXAMPLE 66 N-(3 '-Quinolylcarbonyl)-R-histidine-di-n-pentylamidedihydrochloride

The product of example 29 (800 mg, 1.78 mmol) was dissolved in 13 mL of1.4 N HCl in acetic acid for 10 min and then the volatiles wereevaporated to remove excess reagent. The oily residue was dissolved in asmall amount of CH₂ Cl₂ and the product was precipitated with hexanes.The solid was collected to yield 824 mg, 1.58 mmol (89%). MS(CI) m/e450(m+H)⁺. ¹ H NMR(DMSO_(d6) ,300 MHz) δ 0.74(t,J=7 Hz,3H), 0.85(t,J=7Hz,3H), 1.12-1.32(m,8H), 1.41-1.52(m,4H), 3.08-3.43(m,6H),5.24-5.31(m,1H), 7.45(s,1H), 7.77(dt,J=1,7 Hz,1H), 7.94(dt,J=1,7 Hz,1H),8.15(dt,J=1,9 Hz,2H), 9.02(s,2H), 9.31-9.33(m,2H), 14.18(s,1H),14.57(s,1H). C,H,N analysis calculated for C₂₆ H₃₅ N₅ O₂, 2.6 HCl: C57.36, H 6.96, N 12.87; found: C 57.30, H 6.96, N 12.86.

EXAMPLE 67N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-(4'-hydroxyphenyl)-glycine-di-n-pentylamide

The reaction was performed in a similar manner to that in example 5utilizing 0.3 g of the compound of example 32b,4',8'-dihydroxyquinoline-2-carboxylic acid (0.2 g), EDCI (0.21 g), HOBt(0.13 g) and NMM (0.22 mL). The product was isolated in 75% yield (0.37g). MS(CI) m/e 494(m+H)⁺. ¹ H NMR(DMSO_(d6),300 MHz) δ 0.85(m,6H),1.1-1.35(m,10H), 1.38-1.45(m,4H), 3.0-3.5(m,4H), 5.95(d,J=9 Hz,1H),6.76(d,J=9 Hz,2H), 7.08(d,J=9 Hz,1H), 7.23(d, J=9 Hz,2H), 7.4(t,J=9Hz,1H), 7.55(m,2H), 9.5(bs,1H), 9.75(d,J=10 Hz, 1H). C,H,N calculatedfor C₂₈ H₃₅ N₃ O₅, 0.5 H₂ O: C 66.91, H 7.22, N 8.36; found: C 66.76, H7.20, N 8.18.

EXAMPLE 68 N-(2'-Indolylcarbonyl)-glycine-di-n-pentylamide

Step 68a. N-Benzyloxycarbonyl-glycine-di-n-pentylamide

The compound was prepared in a manner similar to that in example 1autilizing N-t-butyloxycarbonylglycine. MS(CI) m/e 349(m+1)⁺, 305, 241,215, 184. ¹ H NMR(CDCl₃,300 MHz) δ 7.30-740(m,5H), 5.86(bs,1H),5.12(bs,2H), 4.0(bd,J=4.5 Hz,2H), 3.32(t, J=7.5 Hz,2H), 3.15(t,J=7.5Hz,2H), 1.50-1.70(m,4H), 1.20-1.40(m, 8H), 0.9(m,6H).

Step 68b. N-(2'-Indolylcarbonyl)-glycine-di-n-pentylamide

The product of example 68a was deprotected in a manner similar to thatin example 44. The free amine product was then coupled withindole-2-carboxylic acid as in example 2. mp=98°-100° C. MS(EI) m/e357(m)⁺, 287, 184. ¹ H NMR(CDCl₃,300 MHz) δ 9.27(s,1H), 7.67(d,J=6Hz,1H), 7.45(bd,J=7 Hz,2H), 7.29(dt,J=l,6 Hz, 1H), 7.14(dt,J=1,6 Hz,1H),6.98(s,1H), 4.27(d,J=4 Hz,2H), 3.39(bt, J=7 Hz,2H), 3.25(bt,J=7 Hz,2H),1.55-1.70(m,4H), 1.25-1.40(m,8H), 0.93(t,J=6 Hz,3H), 0.91(t,J=6 Hz,3H).C,H,N analysis calculated for C₂₁ H₃₁ N₃ O₂, 0.3 H₂ O: C 69.51, H 8.78,N 11.58; found: C 69.45, H 8.58, N 11.47.

EXAMPLE 69 Ethyl N-(3'-quinolylcarbonyl)glycinyl-(N-benzyl)glycinateStep 69a. Ethyl N-(t-Butyloxycarbony)glycinyl-(N-benzyl) glycinate

N-t-Butyloxycarbonylglycine and ethyl N-benzylglycinate were coupled ina manner similar to that in example 1a to provide product.

Step 69b. Ethyl N-(3'quinolylcarbonyl)glycinyl-(N-benzyl)glycinate

The product of example 69a was deprotected in a manner similar to thatin example 1b and then coupled in a manner similar to that in example 1cto provide product. MS(CI) m/e 406(m+H)⁺, 334, 194. ¹ H NMR(CDCl₃,300MHz) δ 9.37(d,J=2 Hz,0.33H), 9.35(d, J=2 Hz, 0.67H), 8.65(bm,1H),8.18(bd,J=7 Hz,1H), 7.94(m,1H), 7.83 (m,1H), 7.63(m,1H),7.43-7.55(m,1H), 7.30-7.40(m,3H), 7.25(m, 2H), 4.73(s,0.67H),4.67(s,1.33H), 4.51(d,J=4 Hz, 1.33H), 4.33(d, J=4 Hz,0.33H),4.16-4.25(m,2H), 4.13(s,1.33H), 4.00(s,0.67H), 1.28(m,3H).

EXAMPLE 70 N-(3'-Quinolylcarbonyl)-R-homophenylalanine-di-n-pentylamideStep 70a. N-(t-Butyloxycarbonyl)-R-homophenylalanine-di-n-pentyamide

The product was prepared in an analogous manner to that in example 1ausing t-Butyloxycarbonyl-R-homophenylalanine. MS(CI) m/e 419(m+H)⁺, 363,345, 319. ¹ H NMR(CDCl₃,300 MHz) δ 7.85(m,1H), 7.48(m,1H),7.18-7.32(m,5H), 5.39(bd,J=9 Hz,1H), 4.56 (m,1H), 3.48(dt,J=7,14 Hz,1H),3.39(t,J=7 Hz,1H), 3.08(m,2H), 2.68 (m,2H), 1.88(m,2H), 1.45(s,9H),1.20-1.35(m,8H), 1.13(m,2H), 0.88(m,6H).

Step 70b. N-(3'-Quinolylcarbonyl)-R-homophenylalanine-di-n-pentylamide

The product was prepared in analogous manner to those in examples 2 and3 utilizing the product of example 70a as the starting material. MS(CI)m/e 474(m+H)⁺, 369, 319, 305, 289. ¹ H NMR(CDCl₃,300 MHz) δ 9.32(d,J=2Hz,1H), 8.53(d,J=2 Hz,1H), 8.16(bd,J=8 Hz,1H), 7.90(dd,J=l,8 Hz,1H),7.82(m,1H), 7.62(m,1H), 7.40(bd,J=8 Hz,1H), 7.30(m,4H), 7.20(m,1H),5.19(m,1H), 3.55-3.70(m,1H), 3.05-3.20(m,3H), 2.78(bt,J=7.5 Hz,2H),2.15(m,2H), 1.50-1.65(m,4H), 1.15-1.35(m,8H), 0.90(m,6H).

EXAMPLE 71 N-(3'-Quinolylcarbonyl)glycine-di-n-pentylamide Step 71a.N-(3'-Quinolylcarbonyl)glycine

Quinoline-3-carboxylic acid and methyl glycinate hydrochloride werecoupled in a manner similar to that in example 1c. The resulting productwas subjected to saponification in MeOH with 1N NaOH. The desiredproduct was extracted with EtOAc from the acidified solution oralternatively allowed to slowly precipitate from the acidified solution.MS(CI) m/e 231(m+H)⁺, 187. ¹ H NMR(DMSO_(d6),300 MHz) δ 12.72(bs,1H),9.32(d,J=4 Hz,1H), 9.11(t, J=6 Hz,1H), 8.87(d,J=3 Hz,1H), 8.12(t,J=7Hz,2H), 7.89(t,J=7 Hz,1H), 7.71(t,J=7 Hz,1H), 4.03(bs,2H).

Step 71b. N-(3'-Quinolylcarbonyl)glycine-di-n-pentylamide

The product of example 71a and di-n-pentylamine were coupled in a mannersimilar to that in example 1a. The product was isolated bychromatography and solidifies upon concentration. mp=36°-37° C. MS(CI)m/e 370(m+H)⁺. ¹ H NMR(CDCl₃,300 MHz) δ 9.38(d,J=2 Hz,1H), 8.65(d,J=1.8Hz,1H), 8.18(d,J=8.5 Hz,1H), 7.93(dd, J=1,8 Hz,1H), 7.83(m,1H),7.64(m,2H), 4.32(d,J=3.7 Hz,2H), 3.41(bt, J=8 Hz,2H), 3.27(bt,J=8Hz,2H), 1.62(m,4H), 1.30-1.45 (m,8H), 0.95 (t,J=7 Hz,3H), 0.92(t,J=7Hz,3H). C,H,N analysis calculated: C₃₂ H₃₁ N₃ O₂ : C 71.49, H 8.46, N11.37; found: C 71.28, H 8.42, N 11.36.

EXAMPLE 72 N-(3'-Quinolylcarbonyl)glycine-(4-propyl)piperidinylamide

The acid from example 71a and 4-propylpiperdine were coupled as inexample 1a. mp=116°-117° C. MS(CI) m/e 340(m+H)⁺, 279, 254, 201. ¹ HNMR(CDCl₃,300 MHz) δ 9.36(d,J=2 Hz,1H), 8.63(d, J=2 Hz,1H, 8.16(d,J=8.5Hz,1H), 7.93(dd,J=1,8 Hz,1H), 7.82(m,1H), 7.60(bs,1H), 7.63(m,1H),4.61(dt,J=2,13 Hz,1H), 4.31(m,2H), 3.79(bd,J=10 Hz,1H), 3.07(dt,J=3,13Hz,1H), 2.70(dt,J=3,13 Hz,1H), 1.81(bm,2H), 1.55(m, 1H),1.05-1.40(m,6H), 0.92(t,J=7 Hz,3H). C,H,N analysis calculated for C₂₀H₂₅ N₃ O₂, 0.1 H₂ O: C 70.40, H 7.44, N 12.31; found: C 70.19, H 7.44, N12.15.

EXAMPLE 73 N-(3'Quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide Step73a. N-Benzyloxycarbonyl-R-phenylglycine-di-n-pentylamide

The product was obtained from the coupling ofN-Benzyloxycarbonyl-R-phenylglycine and di-n-pentylamine as in example1a. MS(CI) m/e 425(m+H)⁺, 333, 317, 291. ¹ H NMR(CDCl₃, 300 MHz) δ7.27-7.45(m,10H), 6.48(bd,J=7.5 Hz,1H), 5.53(d,J=7.5 Hz, 1H),5.12(d,J=12 Hz,1H), 5.01(d,J=12 Hz,1H), 3.48(m,1H), 3.18(m, 2H),2.97(m,1H), 1.50(m,4H), 1.10-1.35(m,8H), 0.87(t,J=7.5 Hz,3H),0.84(t,J=7.5 Hz,3H).

Step 73b. R-Phenylglycine-di-n-pentylamide

The product resulted from the hydrogenolysis of the product of example73a. MS(CI) m/e 291(m+H)⁺, 158. ¹ H NMR(CDCl₃, 300 MHz) δ7.25-7.40(m,5H), 4.65(bs,1H), 3.52(m,1H), 3.08-3.22(m,2H), 2.92(m,1H),2.02(bs,2H), 1.50(m,3H), 1.10-1.35 (m,9H), 0.88(t,J=7 Hz,3H), 0.85(t,J=7Hz,3H).

Step 73c. N-(3'Quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide

The product of example 73b was coupled in a similar manner to that inexample 1c to provide product. MS(CI) m/e 446(m+H)⁺. ¹ H NMR(CDCl₃,300MHz) δ 9.33(d,J=2 Hz,1H), 8.58(d,J=2 Hz,1H), 8.13(bt,J=8 Hz,2H),7.88(bd,J=8 Hz,1H), 7.79(m,1H), 7.62(m,1H), 7.55(m,2H), 7.32-7.42(m,3H),6.03(d,J=6 Hz,1H), 3.55(m,3H), 1.15-1.40(m,9H), 0.90(t,J=7 Hz,3H),0.86(t,J=7 Hz,3H).

EXAMPLE 74N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide

The product of example 73b was coupled in a similar manner to that inexample 5 to provide the title compound. mp=89°-91° C. MS(CI) m/e478(m+H)⁺, 293, 190, 177. ¹ H NMR(DMSO_(d6), 300 MHz) δ 9.91(bd,J=8Hz,1H), 7.55(m,2H), 7.35-7.45(m,7H), 7.08(dd,J=1,7.5 Hz,1H), 6.11(bd,J=8 Hz,1H), 3.05-3.30(m,4H), 1.60(m,1H), 1.48(m,2H),1.13-1.35(m,9H), 0.85(t,J=7 Hz,3H), 0.78(t,J=7 Hz,3H). C,H,N analysiscalculated for C₂₈ H₃₅ N₃ O₄, 0.3 H₂ O: C 69.63, H 7.43, N 8.70; found:C 69.61, H 7.40, N 8.65.

EXAMPLE 75N-(3'-Chlorophenylaminocarbonyl)-R-phenylglycine-di-n-pentylamide

The product of example 73b was reacted with 3-chlorophenylisocyanate toprovide the title compound. MS(CI) m/e 444(m+H)⁺, 425, 317, 291, 259,242. ¹ H NMR(CDCl₃,300 MHz) δ 7.95(bs,1H), 7.42(m,1H), 7.22-7.34(m,5H),7.13(d,J=7.5 Hz,1H), 7.08(m,2H), 6.89(m,1H), 5.92(d,J=8 Hz,1H),3.50(m,1H), 3.00-3.30 (m,4H), 1.43-1.63(m,3H), 1.10-1.30(m,8H),0.84(t,J=7 Hz,3H), 0.78 (t,J=7 Hz,3H).

EXAMPLE 76N-(3'-Methylphenylaminocarbonyl)-R-phenylglycine-di-n-pentylamide

The product of example 73b was reacted with 3-methylphenylisocyanate toprovide the title compound. MS(CI) m/e 424 (m+H)⁺, 374, 317, 291, 276,239, 228. ¹ H NMR(CDCl₃, 300 MHz) δ 7.27-7.48(m,5H), 7.18(m,1H),7.12(d,J=8 Hz,1H), 7.06(m,2H), 6.82 (bd,J=8 Hz,1H), 6.77(bd,J=8 Hz,1H),5.87(d,J=8 Hz, 1H), 3.51(m,1H), 3.20(m,2H), 3.04(m,1H), 2.28(s,3H),1.50(bm,4H), 1.10-1.30(m, 8H), 0.84(t,J=7 Hz,3H), 0.82(t,J=7 Hz,3H).

EXAMPLE 77 N-(5'-Fluoroindolylcarbonyl)-R-phenylglycine-di-n-pentylamide

The product of example 73b was reacted with 5-fluoroindole-2-carboxylicacid in a manner similar to that in example 2 to provide product.mp=94°-6° C. MS(CI) m/e 452 (m+H)⁺, 276, 267, 184. ¹ H NMR(CDCl₃,300MHz) δ 9.36(bs,1H), 7.96(d,J=7 Hz,1H), 7.50(m,2H), 7.30-7.40(m,3H),7.36(s,1H), 7.33 (m,1H), 6.98(dt, J=2.5,9 Hz,1H), 6.91(m,1H), 5.94(d,J=7Hz,1H), 3.53 (m,1H), 3.13-3.30(m,2H), 3.04(m,1H), 1.45-1.65(m,4H),1.10-1.40 (m,8H), 0.89 (t,J=7 Hz,3H), 0.85(t,J=7 Hz,3H). C,H,N analysiscalculated: C₂₇ H₃₄ FN₃ O₂ : C 71.81, H 7.59, N 9.31; found: C 71.53, H7.50, N 9.30.

EXAMPLE 78 N-(5'-Chloroindolylcarbonyl)-R-phenylglycine-di-n-pentylamide

The product of example 73b was reacted with 5-chloroindole-2-carboxylicacid in a manner similar to that in example 2 to provide the titlecompound. MS(CI) m/e 468(m+H)⁺, 434, 302, 276, 212. ¹ H NMR(CDCl₃,300MHz) δ9.36(bs,1H), 7.97(d,J=7 Hz, 1H), 7.59(m,1H), 7.50(m,2H),7.35(m,3H), 7.22(m,2H), 6.89(m,1H), 5.94(d,J=7 Hz,1H), 3.53(m,1H),3.15-3.30(m,2H), 3.04(m,1H), 1.45-1.60(m,4H), 1.10-1.40(m,8H),0,89(t,J=7 Hz,3H), 0.85(t,J=7 Hz,3H). C,H,N analysis calculated for C₂₇H₃₄ ClN₃ O₂ : C 69.29, H 7.32, N 8.98; found: C 69.44, H 7.36, N 8.95.

EXAMPLE 79 N-(2'-Quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide

The product of example 73b was coupled in a similar manner to that inexample 3 to provide the desired compound. mp=116°-7° C. MS(CI) m/e446(m+H)⁺, 289, 277, 261, 246. ¹ H NMR(CDCl₃, 300 MHz) δ 9.62(d,J=8Hz,1H), 8.24(bs,2H), 8.17(d,J=8 Hz,1H), 7.83(d,J=8 Hz,1H), 7.74(m,1H),7.59(m,3H), 7.30-7.40(m,3H), 6.06(d,J=8 Hz,1H), 3.61(m,1H), 3.32(m,1H),3.0-3.20(m,2H), 1.50-1.65(m,4H), 1.15-1.40(m,8H), 0.89(t,J=7 Hz,3H),0.87(t,J=7 Hz,3H). C,H,N analysis calculated for C₂₈ H₃₅ N₃ O₂ : C75.47, H 7.92, N 9.43; found: C 75.45, H 7.91, N 9.43.

EXAMPLE 80 N'-(3'-Quinolylcarbonyl)-1-amino-cyclohexane-(N-pentyl)carboxamide Step 80a. N'-(t-Butyloxycarbonyl)-1-amino-cyclohexane(N-pentyl) carboxamide

The product was prepared via coupling ofN'-t-Butyloxycarbonyl-1-aminocyclohexane carboxylic acid and pentylamineas in example 1a. MS(CI) m/e 313(m+H)⁺, 257, 239, 213, 198. ¹ HNMR(CDCl₃,300 MHz) δ 6.70(s,1H), 4.52(bs,1H), 3.23(m,2H),1.80-2.05(m,4H), 1.65(m,4H), 1.44(s,9H), 1.25-1.38(m,8H), 0.88 (t,J=7Hz,3H).

Step 80b. N'-(3'-Quinolylcarbonyl)-1-amino-cyclohexane-(N-pentyl)carboxamide

The product was obtained in a similar manner to that in examples 1b and1c using the product of example 80a as the starting material. MS(CI) m/e368(m+H)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ 9.38(d,J=2 Hz, 1H), 8.58(d,J=2Hz,1H), 8.18(d,J=8 Hz,1H), 7.94(bd,J=8 Hz,1H), 7.83 (m,1H), 7.65(m,1H),7.12(bs,1H), 6.27(bs,1H), 3.38(m,2H), 2.34 (m,2H), 2.03(m,2H),1.65-1.80(m, 4H), 1.50-1.60(m,4H), 1.25-1.40 (m,4H), 0.88(t,J=7 Hz,3H).C,H,N analysis calculated for C₂₂ H₂₉ N₃ O₂ : C 71.91, H 7.95, N 11.43;found: C 71.73, H 7.95, N 11.33.

EXAMPLE 81N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)glycine-di-n-pentylamide

The product of example 68a was deprotected in a manner similar to thatin example 44 and the resulting amine was then coupled in a mannersimilar to that in example 5 to yield the title compound.mp=158.5°-159.5° C. MS(FAB) m/e 402(m+H)⁺, 386, 245, 217. ¹ HNMR(DMSO_(d6),300 MHz) δ 9.90(bs,1H), 9.80(bs,1H), 7.55(bt,J=8 Hz,1H),7.52(bs,1H), 7.42(m,1H), 7.11(bd,J=8 Hz,1H), 4.20(bd,J=6 Hz,2H),3.36(bs,H₂ O), 3.20-3.33(m,4H), 1.58(m,2H), 1.48(m,2H), 1.20-1.33(m,8H),0.85(m,6H). C,H,N analysis calculated for C₂₂ H₃₁ N₃ O₄, H₂ O: C 62.99,H 7.93, N 10.02; found: C 63.12, H 8.02, N 10.01.

EXAMPLE 82 N-(2 '-Naphthoyl)glycine-di-n-pentylamide

The product of example 68a was deprotected in a manner similar to thatin example 44 and the resulting amine was then coupled in a mannersimilar to that in example 11 to yield the title compound. MS(CI) m/e369(m+H)⁺, 200, 184, 172. ¹ H NMR (CDCl₃,300 MHz) δ 8.38(s,1H),7.85-7.95(m,4H), 7.50-7.60 (m,3H), 4.30(d,J=4 Hz,2H), 3.40(t,J=7.5Hz,2H), 3.26(t,J=7.5 Hz,2H), 1.60(m, 4H), 1.25-1.45(m,8H), 0.94(t,J=7Hz,3H), 0.92(t,J=7 Hz,3H). C,H,N analysis calculated for C₂₃ H₃₂ N₂ O₂ :C 74.96, H 8.75, N 7.68; found: C 74.44, H 8.75, N 7.55.

EXAMPLE 83 N-(6'-Hydroxy-2'-naphthoyl)glycine-di-n-pentylamide

The product of example 68a was deprotected in a manner similar to thatin example 44 and the resulting amine was then coupled with6-hydroxy-2-naphthoic acid in a manner similar to that in example 11 toyield the title compound. MS(CI) m/e 385(m+H)⁺, 228, 200, 184. ¹ HNMR(DMSO_(d6),300 MHz) δ 8.58(bt,J=6 Hz,1H), 8.36(bs,1H), 7.86(m,2H),7.63(d,J=8 Hz,1H), 7.15(m,2H), 4.14(d, J=5 Hz,2H), 3.20-3.35(m,4H),1.60(m,2H), 1.45(m,2H), 1.20-1.35 (m,8H), 0.89(t,J=7 Hz,3H), 0.86(t,J=7Hz,3H). C,H,N analysis calculated for C₂₃ H₃₂ N₂ O₃ : C 71.84, H 8.39, N7.29; found: C 71.73, H 8.36, N 7.21.

EXAMPLE 84 N-(3'-Methylphenylaminocarbonyl)glycine-di-n-pentylamide

The product of example 68a was deprotected in a manner similar to thatin example 44 and the resulting amine was then coupled with3-methylphenylisocyanate to yield the title compound. mp=66°-7° C.MS(CI) m/e 348(m+H)⁺, 241, 215, 200, 184. ¹ H NMR (CDCl₃,300 MHz) δ7.08-7.20(m,3H), 7.03(bs,1H), 6.86(bd,J=7 Hz, 1H), 6.21(bs,1H),4.13(bs,2H), 3.32(bt,J=7.5 Hz,2H), 3.21(bt, J=7.5 Hz,2H), 2.30(s,3H),1.45-1.65(m,4H), 1.20-1.40(m,8H), 0.92(t, J=7 Hz,3H), 0.86(t,J=7 Hz,3H).C,H,N analysis calculated for C₂₀ H₃₃ N₃ O₂ : C 69.13, H 9.57, N 12.09;found: C 68.99, H 9.56, N 12.04.

EXAMPLE 85 N-(2'-Chlorophenylaminocarbonyl)-(2R,3S)-(O-benzyl)threonine-di-n-pentylamide

The reaction was performed in a similar manner as in the above exampleutilizing 0.35 g of the hydrochloride salt of example 19b,2-chlorophenylisocyanate (0.16 g), and TEA (0.135 mL). The product waspurified using CHCl₃ and MeOH as the elutant mixture. The oily productwas isolated in 83% yield (0.42 g). [α]_(D) =+21.8° (c=0.11, MeOH).MS(CI) m/e 502(m+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ 0.85(m,6H), 1.23(m,11H),1.43-1.65(m,4H), 3.0-3.21(m,2H), 3.55(m,2H), 3.33(m,1H), 4.57(d,J=15Hz,1H), 4.63 (d,J=15 Hz,1H), 4.98(m,1H), 6.48(d,J=9 Hz,1H), 6.95(t,J=7Hz,1H), 7.2(m,2H), 7.3(m,6H), 8.11(d,J=9 Hz,1H). C,H,N analysiscalculated for C₂₈ H₄₀ ClN₃ O₃, 0.3 CHCl₃ : C 63.19, H 7.55, N 7.81;found: C 63.21, H 7.34, N 7.82.

EXAMPLE 86N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-(2R,3S)-(O-benzyl)-Threonine-di-n-pentylamide

The reaction was performed in a similar manner as in example 5 utilizing0.35 g of the hydrochloride salt of example 19b4,8-dihydroxyquinoline-2-carboxylic acid (0.21 g), EDCI (0.22 g), HOBt(0.14 g), and NMM (0.22 g). The oily product was isolated in 60% yield(0.32 g). [α]_(D) =+8.0° (c=0.125, MeOH). MS(CI) m/e 536(m+H)⁺. ¹ HNMR(DMSO_(d6),300 MHz) δ 0.82(m,6H), 1.15-1.3(m, 11H), 1.4-1.6(m,4H),3.2-3.65(m,4H), 4.08(m,1H), 4.52(d, J=12 Hz,1H), 4.63(d,J=12 Hz,1H),4.98(t,J=9 Hz,1H), 7.12(m,5H) 7.42 (t,J=9 Hz,1H), 7.55(m,2H), 9.8(d,J=9Hz,1H), 10.4(bs,1H), 11.72(bs, 2H). C,H,N analysis calculated for C₃₁H₄₁ N₃ O₅, H₂ O: C 67.25, H 7.83, N 7.59; found: C 67.19, H 7.60, N7.38.

EXAMPLE 87 MethylN-(3'-quinolylcarbonyl)-R-methionine-S-(p-hydroxy)-phenylglycinate Step87a. Methyl Boc-R-methionine-S-(p-hydroxy)-phenylglycinate

Boc-R-methionine (250 mg, 1 mmol), methyl p-hydroxyphenylglycinatehydrochloride (217 mg, 1 mmol) and TEA (139 μL, 1 mmol) were combined in10 mL of dichloromethane at 0° C. and treated with BOPCl (254 mg,lmmol). Additional BOPCl (254 mg) and TEA (134 μL) were added after oneday. After two days, the reaction mixture was poured into EtOAc andextracted successively with 0.1% citric acid, 0.1M NaHCO₃ and water. Thesolution was then dried over MgSO₄, filtered and evaporated to yield 288mg, 0.7 mmol (70%). Rf=0.56 (1:1 hexanes - EtOAc). mp=158° C. (dec).MS(CI) m/e 413(m+H)⁺, 357, 313. ¹ H NMR (CDCl₃,300 MHz) d 1.43(s,9H),3.72(s,3H), 6.73(d,J=8 Hz,2H), 7.17(d,J=8 Hz,2H), 7.33(bs,1H).

Step 87b. Methyl R-methionine-S-(p-hydroxy)-phenylglycinatehydrochloride

The product of the example 87a (250 mg, 0.6 mmol) was treated with 5 mLof 4 N HCl in dioxane at room temperature under a nitrogen atmosphere.After 30 minutes, the excess reagent was evaporated to yieldquantitatively the product.

Step 87c. MethylN-(3'-quinolylcarbonyl)-R-methionine-S-(p-hydroxy)-phenylglycinate

The hydrochloride salt of example 87b (50 mg, 0.14 mmol), 3-quinolinecarboxylic acid (26 mg, 0.15 mmol) and TEA (21 μL, 0.15 mmol) weredissolved into 5 mL CH₂ Cl₂ and treated with EDCI (29 mg, 0.15 mmol) for4 hours. The reaction was poured into EtOAc and extracted with 0.1%citric acid and water followed by drying over MgSO4. The resultantfiltrate was concentrated and chromatographed over silica gel elutingwith a 2:1 to 1:2 hexane - EtOAc gradient to yield 29 mg, 0.06 mmol(44%). MS(CI) m/e 468(m+H)⁺, 393, 287. ¹ HNMR(CDCl₃,300 MHz) δ2.04(s,3H), 2.12-2.20(m,2H), 2.42-2.52(m,1H), 2.57-2.67(m,1H),3.65(s,3H), 5.05(q,J=7 Hz,1H), 5.41(d,J=6 Hz,1H), 6.77(d,J= 8 Hz,2H),7.16(d, J=8 Hz,2H), 7.59(dt,J=1,7 Hz,1H), 7.73-7.82(m,3H), 7.83(d,J=8Hz, 1H), 8.12(d,J=8 Hz,1H), 8.61(d,J=2 Hz,1H), 9.30(d, J=2 Hz,1H). C,H,Nanalysis calculated for C₂₄ H₂₅ N₃ O₅ S 0.5 H₂ O: C 60.49, H 5.60, N8.81; found: C 60.64, H 5.63, N 8.35.

EXAMPLE 88 N-(3'-Quinolylcarbonyl)-R-serine-di-n-pentylamide

BTFA (trifluoroacetoxyboronate) 0.154 g, 0.4 mmol was added to theproduct of example 17c (71 mg, 0.145 mol) dissolved in 2 mL of CH₂ Cl₂.Another mL of CH₂ Cl₂ was added and the reaction was monitored by tlc.After 20 minutes of stirring at ambient temperature, the startingmaterial was consumed and the solvents with MeOH were evaporated undervacuum. This evaporation sequence using MeOH was repeated several times.The residue was separated by chromatography using EtoAc-hexane (1:1) asthe elutants. An oily product was isolated in 69% yield (40 mg). MS(CI)m/e 400 (m+H)⁺. ¹ HNMR(CD₃ OD,300 MHz) δ 0.94 (m,6H), 1.26-1.44 (m,8H),1.54-1.64(m,2H), 1.68-1.86(m,3H), 3.25-3.35(m,1H), 3.43-3.62(m,3H),3.82-3.96(m,2H), 5.22(t,J=6 Hz, 1H), 7.73(t,J=6 Hz,1 H), 7.91(t,J=6Hz,1H), 8.07(d,J=9 Hz,1H), 8.12(d, J=9 Hz,1H), 8.9(s,1H), 9.28(s,1H).

EXAMPLE 89 N-(8'-Hydroxy-2-quinolylcarbonyl)-glycine-di-n-pentylalamide

Similar to example 68b, the product of example 68a was deprotected andcoupled to 8-hydroxy-2-quinolinic carboxylic acid in a standard fashionutilizing EDCI etc. to provide the product. MS(CI) m/e 386 (m+H)⁺. ¹HNMR(CDCl₃,300 MHz) δ 8.96(bs,1H), 8.23(s,2H), 8.02(s,1H), 7.53(t,J=7.5Hz,1H), 7.36(dd, J=1,7.5 Hz,1H), 7.23(dd,J=1,7.5 Hz, 1H), 4.34(d,J=5Hz,2H), 3.42(bt, J=8 Hz,2H), 3.28(bt,J=8 Hz,2H), 1.55-1.70(m,4H),1.25-1.40(m,8H), 0.93(apparent q,6H). C,H,N analysis calculated for C₂₂H₃₁ N₃ O₃ 0.2 H₂ O: C 67.91, H 8.13, N 10.80; found: C 67.90, H 8.14, N10.69.

EXAMPLE 90 N-Methyl-N-(3'quinolylcarbonyl)-glycine-di-n-pentylamide

The product of example 71b was methylated using bistrimethylsilylamideand methyl iodide in THF at -78° C. warming to ambient temperature toprovide product after standard workup and purification. MS(DCI) m/e384(m+H)⁺.

EXAMPLE 91 N-(3'-Iodo-2'-indolylcarbonyl)-glycine-di-n-pentylamide

The product of example 68b was iodinated with N-iodo-succinimide toprovide product after chromatographic purification. MS(DCI) m/e484(m+H)⁺. C,H,N analysis calculated for C₂₁ H₃₀ IN₃ O₂ : C 52.18, H6.25, N 8.69; found: C 52.04, H 6.21, N 8.49.

EXAMPLE 92 N-(2'-Indolylcarbonyl)-R-alanine-di-n-pentylamide

In a similar fashion to example 1 the product was prepared from thecorresponding R-alanyl-di-n-pentylamide hydrochloride and 3-quinolinecarboxylic acid to yield product. MS(CI) m/e 372(m+H)⁺. C,H,N analysiscalculated for titled product: C 71.1, H 8.95, N 11.31; found: C 70.76,H 9.03, N 11.17.

EXAMPLE 93 N-(2'-Indolylcarbonyl)-R-methioninesulfoxide-di-n-pentylamide

In a similar manner to examples 54 and 55 the product was prepared usingthe trifluoroacetate salt of example 54b and indolyl-2-carboxylic acid.

EXAMPLE 94N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidideStep 94a.N-(t-Butyloxycarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide

N-(t-Butyloxycarbonyl)-(β-O-benzyl)-R-serine (2.79 g, 9.45 mmol),4-benzoylpiperidine hydrochloride (2.13 g, 9.45 mmol), HOBt (1.59 g,10.40 mmol), and N-methylmorpholine (NMM) (1.56 mL, 14.18 mmol) weredissolved in 20 mL anhydrous CH₂ Cl₂ :DMF (1:1). The mixture was cooledto ice bath temperature and EDCI (1.99 g, 10.40 mmol) was added inportions over 15 min. The reaction was allowed to stir at ice bathtemperature for 3 h and then allowed to warm to ambient temperature overan additional 3 h, whereupon ethyl acetate and saturated aqueous NaHCO₃were added. The aqueous portion was extracted three times with ethylacetate, and the combined organic extractions were washed twice withsaturated aqueous NaHCO₃, twice with saturated aqueous KHSO₄, and oncewith brine. The solution was then dried over Na₂ SO₄, filtered, and thevolatile components were evaporated. Following silica gelchromatography, EtOAc: hexane (1:1), fractions judged to be pure werepooled, and the volatile components were evaporated to give the titlecompound as a white solid (4.14 g, 8.88 mmol) in 94% yield. MS(CI) m/e467 (M+H)⁺. NMR (CDCl₃,300 MHz) δ: 1.43 (s,9H), 1.49-1.97 (m,4H), 2.93(m,1H), 3.18 (m,1H), 3.45 (m,1H), 3.46-3.68 (m,2H), 4.05 (m,1H),4.46-4.61 (m,3H), 4.87 (m,1H), 5.51 (m,1H)7.27-7.36 (m,5H), 7.45-7.53(m,2H), 7.57 (m,1H), 7.88-7.94 (m,2H).

Step 94b.N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide

The product of example 94a (235 mg, 0.50 mmol) was treated with 2 mL of45% trifluoroacetic acid (TFA) in CH₂ Cl₂ for approximately 2 hwhereupon the solution was concentrated in vacuo. CH₂ Cl₂ was added andevaporated several times to complete TFA removal. The resultingR-serine-4'-benzoylpiperidide trifluoroacetate was dissolved inanhydrous CH₂ Cl₂ (1 mL) and NMM (0.083 mL, 0.76 mmol) and treated withm-tolyl isocyanate (0.065 mL, 0.50 mmol). After 0.5 h the reaction wassubjected to extractive work-up and silica gel chromatography followingprocedures described in example 94a to give the title compound as awhite solid (113 mg, 0.23 mmol) in a 45% yield. MS(CI) m/e 500 (M+H)⁺.NMR (CDCl₃,300 MHz) δ: 1.57-1.98 (m,4H), 2.28 (s,3H), 3.01 (m,1H), 3.28(m,1H), 3.42-3.71 (m,3H), 4.11 (m,1H), 4.47 (s,2H), 4.58 (m,1H), 5.20(m,1H), 6.49 (br s,1H), 6.82 (m,1H), 7.13 (m,3H), 7.18-7.32 (m,6H,obscured), 7.4 (m,1H), 7.45 (m,2H), 7.57 (m,1H), 7.92 (m,1H). C, H, Nanalysis calculated for C₃₀ H₃₃ N₃ O₄ : C 72.12, H 6.66, N 8.41; found:C 72.08, H 6.54, N 8.20.

EXAMPLE 95N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-Aspartyl-4'-benzoylpiperidideStep 95a.N-(t-Butyloxycarbonyl)-(β-O-benzyl)-R-Aspartyl-4'-benzoylpiperidide

N-(t-Butyloxycarbonyl)-(β-O-benzyl)-R-aspartic acid was converted to thetitle compound using the procedure of example 94a. MS(CI) m/e 495(M+H)⁺, 512 (M+NH₄)⁺. NMR (CDCl₃,300 MHz) δ 1.43 (s,9H), 1.44-1.98(m,4H), 2.65 (m,1H), 2.77-3.04 (m,2H), 3.23 (m,1H), 3.49 (m,1H), 4.14(br t,J=18 Hz,1H), 4.47 (br dd,J=15 Hz,30 Hz,1H), 5.02 (m,1H), 5.11(s,2H), 5.42 (m,1H), 7.31-7.38 (m,5H), 7.45-7.53 (m,2H), 7.57 (m,1H),7.90-7.997 (m,2H).

Step 95b.N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-Aspartyl-4'-benzoylpiperidide

The title compound was prepared from the product of example 95a usingthe procedure of example 94b. MS(CI) m/e 528 (M+H)⁺. NMR (CDCl₃,300 MHz)δ 1.54-1.79 (m,2H), 1.80-2.03 (m,2H), 2.29 (s,3H), 2.77 (m,1H),2.83-3.07 (m,2H), 3.19-3.62 (m,2H), 4.23 (br d,J=15 Hz,1H), 4.44 (brt,J=12 Hz,1H), 5.04-5.17 (m,2H), 5.35 (m,1H), 6.24 (m,1H), 6.83 (d,J=7.5Hz,1H), 7.07-7.34 (m,9H), 7.44-7.53 (m,2H), 7.57 (m,1H), 7.93(dd,J=7.5,15 Hz,2H). C, H, N analysis calculated for C₃₁ H₃₃ N₃ O₅ : C70.57, H 6.30, N 7.96; found: C 70.39, H 6.01, N 7.80.

EXAMPLE 96N-(m-Toluylaminocarbonyl)-γ-pyrrolidin-1-yl)-R-Glutamyl-4'-benzoylpiperidideStep 96a.N-(t-Butyloxycarbonyl)-γ-O-benzyl)-R-Glutamyl-4'-benzoylpiperidide

N-(t-Butyloxycarbonyl)-γ-O-benzyl)-R-glutamic acid was converted to thetitle compound using the procedure of example 94a. MS(CI) m/e 509(M+H)⁺. NMR (CDCl₃,300 MHz) δ: 1.43 (s,9H),1.60-1.87 (m,3H), 1.88-2.13(m,3H), 2.37-2.64 (m,2H), 2.92 (br dd,J=12,18 Hz,1H), 3.24 (br t,J=13.5Hz,1H), 3.51 (m,1H), 4.13 (br t,J=15 Hz,1H), 4.51 (br d,J=13.5Hz,1H)4.24 (m,1H), 5.09-5.19 (m,2H), 5.48 (m,1H), 7.28-7.40 (m,5H),7.45-7.53 (m,2H), 7.58 (m,1H), 7.94 (d,J=9 Hz, 1H).

Step 96b.N-(m-Toluylaminocarbonyl)-(γ-O-benzyl)-R-Glutamyl-4'-benzoylpiperidide

The title compound was prepared from the product of example 96a by theprocedure of example 94b. MS(CI) m/e 542 (M+H)⁺. NMR (CDCl₃,300 MHz) δ:1.68-2.17 (m,6H), 2.30 (s,3H), 2.48 (m,1H), 2.60 (m,1H), 2.97 (brdd,J=13.5,19.5 Hz, 1H), 3.32 (m,1H), 3.53 (m,1H), 4.19 (br t,J=15 Hz,1H), 4.49 (m,1H), 5.05 (m,1H), 5.14 (s,2H), 6.21 (d,J=9 Hz,1H), 6.84(m,1H), 6.97 (d,J=18 Hz,1H), 7.05-7.22 (m,3H), 7.25-7.43 (m,5H),7.47-7.53 (m,2H), 7.60 (m,1H), 7.89-7.98 (m,2H). C, H, N analysiscalculated for C₃₂ H₃₅ N₃ O₅ : C 70.96, H 6.51, N 7.76; found: C 70.91,H 6.54, N 7.42.

Step 96c.N-(m-Toluylaminocarbonyl)-(γ-pyrrolidin-1-yl)-R-Glutamyl-4'-benzoylpiperidide

The product of example 96b (212 mg, 0.39 mmol) in MeOH (2 mL) wastreated with 2N NaOH (0.25 mL, 0.5 mmol), and the mixture was stirred atambient temperature overnight. The acidic component was isolated bystandard extractive proceures to afford 150 mg of the carboxylic acid. Asolution of the above acid, pyrrolidine (0.026 mL, 0.34 mmol), andtriethylamine in CH₂ Cl₂ (3 mL) at 0° C. was treated with BOP-Cl. Themixture was allowed to warm slowly to ambient temperature and stir for 2days. The crude product from acid-base work-up was purified bychromatography (silica gel, 97:3 EtOH/CHCl₃) to afford 115 mg (74%) ofthe product as an oily residue which was lyophilized from EtOH/H₂₀ toform a fluffy powder. ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.7-2.0 (m, 8H), 2.15(m, 2H), 2.30 (s, 3H), 2.35 (m, 1H), 2.51 (m, 1H), 2.96 (m, 1H),3.30-3.60 (m, 6H), 4.30 (m, 1H), 4.40-4.60 (m, 2H), 4.98 (m, 1 H,exchangeable), 6.29 (m, 1H, exchangeable), 6.80 (t, J=6 Hz, 1H),7.05-7.21 (m, 3H), 7.49 (m, 2H), 7.58 (m, 1H), 7.92 (m, 2H). MS (CI) m/e505 (M +H)⁺. CHN analysis calculated for: C₂₉ H₃₆ N₄.0.2 H₂ O: C 68.54,H 7.21, N 11.02; found: C 68.50, H 7.04, N 10.80

EXAMPLE 97N-(m-Methoxyphenylaminocarbonyl)-γ-pyrrolidin-1-yl)-R-Glutamyl-4'-benzoylpiperidideStep 97a.N-(m-Methoxyphenylaminocarbonyl)-γ-O-benzyl)-R-Glutamyl-4'-benzoylpiperidide

The title compound was prepared from the product of example 96a by theprocedure of example 94b, substituting m-methoxyphenylisocyanate form-toluylisocyanate. ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.65-2.20 (m, 6H),2.40-2.60 (m, 2H), 2.98 (m, 1H), 3.32 (m, 1H), 3.52 (m, 1H), 3.77 (s,3H), 4.20 (m, 1H), 4.50 (m, 1H), 5.02 (m, 1H), 5.12 (s, 2H), 6.58 (m,1H), 6.80 (m, 1H), 6.95-7.10 (m, 2H), 7.13 (m, 1H), 7.22-7.42 (m, 6H),7.50 (m, 2H), 7.60 (m, 1H), 7.92 (m, 2H). MS (CI) m/e 558 (M+H⁺). CHNanalysis calculated for: C₃₂ H₃₅ N₃ O₆. 1.7 H₂ O: C 65.34, H 6.58, N7.14; found: C 65.27, H 5.98, N 6.99.

Step 97b. N-(m-Methoxyphenylaminocarbonyl)-(γ-pyrrolidin-1-yl)-R-Glutamyl-4'-benzoylpiperidide

The title compound was prepared from the product of example 97a usingthe procedure of example 96c. 1H-NMR (CDCl₃, 300 MHz) δ: 1.70-2.05 (m,8H), 2.15 (m, 2H), 2.35 (m, 1H), 2.51 (m, 1H), 2.96 (m, 1H), 3.30-3.60(m, 6H), 3.79 (s, 3H), 4.30 (m, 1H), 4.44 (m, 1H), 4.52 (m, 1H), 4.97(m, 1H), 6.25 (m, 1H), 6.55 (m, 1H), 6.81 (m, 1H), 7.12 (m, 2H), 7.49(m, 2H), 7.59 (m, 1H), 7.91 (d, J=7.5 Hz, 1H). MS (CI) m/e 521 (M+H⁺).CHN analysis calculated for: C₂₉ H₃₆ N₄ O₅.0.5 H₂ O: C 65.77, H 7.04, N10.58; found: C 65.88, H 6.71, N 10.58.

EXAMPLE 98 N-(2-Adamantyloxycarbonyl)-(γ -O-benzyl)-R-Glutamyl-4'-benzoylpiperidide

The title compound was prepared from the product of example 96a by theprocedure of example 94b substituting 2-adamantyloxychloroformate form-toluylisocyanate and anhydrous DMF for CH₂ Cl₂. MS(CI) m/e 587 (M+H)⁺.NMR (CDCl₃,300 MHz) δ: 1.46-1.60 (m,3H), 1.65-1.87 (m,10H), 1.88-2.10(m,7H), 2.38-2.64 (m,2H), 2.92 (m,1H), 3.24 (m,1H), 3.51 (m,1H), 4.12(br t,J=13.5 Hz, 1H), 4.51 (m, 1H), 4.73-4.85 (m,2H), 5.13 (s,2H), 5.68(br t,J=7.5 Hz, 1H), 7.26-7.38 (m,5H), 7.45-7.54 (m,2H), 7.59 (m, 1H),7.90-7.97 (m,2H). C, H, N analysis calculated for C₃₅ H₄₂ N₂ O₆ : C71.65, H 7.21, N 4.77; found: C 71.38, H 7.12, N 4.42.

EXAMPLE 99 N-(Phenylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide

The product of example 94a was converted to the title compound by theprocedure of example 94b, substituting phenyl isocyanate form-toluylisocyanate. MS(CI) m/e 486 (M+H)⁺. NMR (CDCl₃,300 MHz) δ:1.55-1.98 (m,4H), 3.02 (m,1H), 3.29 (m, 1H), 3.47 (m,1H), 3.55-3.69(m,2H), 4.11 (m,1H), 4.47 (s,2H), 4.52 (m,1H), 5.21 (m,1H), 6.51 (brs,1H), 7.0 (t,J=7.5 Hz,1H), 7.20-7.38 (m,9H), 7.44-7.55 (m,3H), 7.58(m,1H), 7.91 (m,1H). C, H, N analysis calculated for C₂₉ H₃₁ N₃ O₄ : C71.73, H 6.43, N 8.65; found: C 71.85, H 6.46, N 8.51.

EXAMPLE 100N-(m-Methoxyphenylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide

The product of example 94a was converted to the title compound by theprocedure of example 94b, substituting m-methoxyphenyl isocyanate form-toluylisocyanate. MS(CI) m/e 516 (M+H)⁺. NMR (CDCl₃,300 MHz) δ:1.57-1.99 (m,4H), 3.02 (m, 1H), 3.28 (m, 1H), 3.43-3.68 (m,3H), 3.77(s,3H), 4.11 (m,1H), 4.48 (s,2H), 4.57 (m, 1H), 5.21 (m, 1H), 6.54 (brd,J=9 Hz,2H), 6.78 (dd,J=3,9 Hz, 1H), 7.07-7.17 (m,2H), 7.21-7.31(m,5H), 7.41-7.51 (m, 3H), 7.57 (m, 1H), 7.86-7.93 (m,2H). C, H, Nanalysis calculated for C₃₀ H₃₃ N₃ O₅ : C 69.88, H 6.45, N 8.15; found:C 69.58, H 6.43, N 8.00.

EXAMPLE 101 N-(m-chlorophenylaminocarbonyl)-(γ-O-benzyl)-R-serine-4'-benzoylpiperidide

The product of example 94a was converted to the title compound by theprocedure of example 94b, substituting m-chlorophenyl isocyanate form-toluylisocyanate. MS(CI) m/e 520, 522 (M+H)⁺. NMR (CDCl₃,300 MHz) δ:1.63-2.05 (m,4H), 3.10 (m, 1H), 3.33 (m, 1H), 3.50 (m,1H), 3.55-3.67(m,2H), 4.10 (m, 1H), 4.44 (s,2H), 4.55 (m,1H), 5.19 (m,1H), 6.68 (brs,1H), 6.92 (m, 1H), 7.07-7.20 (m,2H), 7.21-7.29 (m,5H), 7.37 (m, 1H),7.43-7.51 (m,2H), 7.57 (m,1H), 7.75 (br d,J=25.5 Hz, 1H), 7.90 (t,J=7.5Hz,2H). C, H, N analysis calculated for C₂₉ H₃₀ N₃ O₄ Cl: C 66.98, H5.81, N 8.08; found: C 66.78, H 5.53, N 7.91.

EXAMPLE 102N-(m-acetylphenylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-benzoylpiperidide

The product of example 94a was converted to the title compound by theprocedure of example 94b, substituting m-acetylphenyl isocyanate form-toluylisocyanate. MS(CI) m/e 520, 522 (M+H)⁺. NMR (CDCl₃,300 MHz) δ:1.57-2.05 (m,4H), 2.55 (s,3H), 3.11 (m, 1H), 3.31 (m, 1H), 3.53 (m, 1H),3.57-3.71 (m,2H), 4.13 (m, 1H), 4.45 (s,2H), 4.53 (m, 1H), 5.21 (m, 1H),7.18-7.37 (m,7H), 7.45-7.68 (m,5H), 7.85 (d,J=10.5 Hz,1H)), 7.90-7.98(m,3H). C, H, N analysis calculated for C₃₁ H₃₃ N₃ O₅ : C 70.57, H 6.30,N 7.96; found: C 70.29, H 6.43, N 7.70.

EXAMPLE 103N-(m-Toluylaminocarbonyl)-(S-benzyl)-S-Cysteine-4'-benzoylpiperidideStep 103a. N-(t-Butyloxycarbonyl)-(S-benzyl)-S-Cysteine-4'-benzoylpiperidide

To a stirred solution of N-(t-Butyloxycarbonyl)-(S-benzyl)-S-cysteine(200 mg, 0.64 mmol), 4-benzoylpiperidide hydrochloride (145 mg, 0.64mmol),and triethylamine (0.27 mL, 1.9 mmol) in methylene chloride (5 mL)at 0° C. was added BOP-CI. The mixture was allowed to warm slowly toambient temperature and stir for 2 days. Acid-base work-up followed bychromatography (silica gel, 2:1 hexane/EtOAc) afforded the titlecompound (193 mg, 59%). ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.46 (s, 9H),1.5-2.0 (m, 4H), 2.58 (m, 1H), 2.73 (m, 1H), 2.92 (m, 1H), 3.12 (m, 1H),3.49 (m, 1H), 3.77 (m, 2H), 3.85 (m, 1H), 4.50 (d, J=13 Hz, 1H), 4.78(m, 1H), 5.40 (m, 1H), 7.15-7.39 (m 5H), 7.50 (m, 2H), 7.59 (m, 1H),7.92 (d, J=7.5 Hz, 1H). MS (CI) m/e 483 (M+H⁺).

Step 103b.N-(m-Toluylaminocarbonyl)-(S-benzyl)-S-Cysteine-4'-benzoylpiperidide

The title compound was prepared from the product of example 103a usingthe procedure of 94b. ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.7-2.0 (m, 4H), 2.30(s, 3H), 2.60-2.87 (m, 2H), 2.98 (m, 1H), 3.20 (m, 1H), 3.50 (m, 1H),3.75 (dd, J=13.18 Hz, 1H), 3.95 (m, 1H), 4.48 (m, 1H), 5.12 (m, 1H),6.32 (m, 1H), 6.81 (d, J=7.5 Hz, 1H), 7.06-7.36 (m, 5H}, 7.49 (m, 2H),7.60 (m, 1H), 7.91 (m, 2H). MS (CI) m/e 516 (M+H⁺). CHN analysiscalculated for: C₃₀ H₃₃ N₃ O₃ S: C 69.88, H 6.45, N 8.01, S 6.22: found:C 69.73, H 6.70, N 8.01, S 6.25

EXAMPLE 104N-(m-Toluylaminocarbonyl)-(S-benzyl-S,S-dioxo)-S-Cysteine-4'-benzoylpiperidide

The product of example 103b (105 mg, 0.20 mmol) in HOAc (2 mL) wastreated with 0.02 mL of 30% aq. H₂ O₂. After stirring for 40 h, themixture was subjected to standard acid-base work-up, and the crudeproduct was chromatographed (silica gel, 97:3 CHCl₃ /MeOH) to afford 11mg of product. After combining with an additional 20 mg obtainedsimilarly, crystallization from Et₂ /hexane afforded 20 mg of the titlecompound. ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.75 (m, 2H), 1.92 (m, 2H), 2.30(s, 3H), 3.0 (m, 1H), 3.22-3.46 (m, 3H), 3.51 (rn, 1H), 4.06 (m, 1H),4.40 (s, 2H), 4.42 (m, 1H), 5.50 (m, ! H), 6.18 (ra, 1H), 6.89 (d, J=7.5Hz, 1H), 7.05-7.21 (m, 4H), 7.37 (m, 3H), 7.45 (m, 4H), 7.58 (m, 1H),7.92 (m, 2H). MS (CI) m/e 547 (M+H⁺). CHN analysis calculated for: C₃₀H₃₃ N₃ O₅ S. H₂ O: C 63.70, H 6.24, N 7.43; found: 63.81, 6.24, 7.43.

EXAMPLE 105N-(m-Toluylaminocarbonyl)-(S-benzyl-S-oxo)-S-Cysteine-4'-benzoylpiperidide

Continued elution of the column from example 104 afforded 62 mg of thetitle compound. Trituration with EtOAc afforded 15 mg of the product ascolorless crystals. 1H-NMR (DMSO-d6, 300 MHz) δ: 1.20-1.56 (m, 2H),1.70-1.90 (m, 2H), 2.23 (s, 3H), 2.70-2.96 (m, 3H), 3.22 (m, 1H), 3.70(m, 1H), 3.90 (m, 1 H), 4.02 (d, J=5 Hz, 0.5H), 4.06 (d, J=5 Hz, 0.5H),4.20 (d, J=3 Hz, 0.5H), 4.25 (d, J=0.5H), 4.35 (m, 1H), 5.11 (m, 1H),6.62 (m 1H, exchangeable), 6.72 (d, J=7 Hz, 1H), 7.11 (m, 2H), 7.22 (m,2H), 7.35 (m, 4H), 7.55 (m, 2H), 7.65 (m, 1H), 8.02 (m, 2H), 8.65 (s,0.5 H, exchangeable), 8.70 (s, 0.5 H, exchangeable). MS (CI) m/e 532(M+H⁺). CHN analysis calculated for: C₃₀ H₃₃ N₃ O₄ S. 0.8 H₂ O: C 65.99,H 6.39, N 7.69; found: C 65.79, H 6.00, N 7.58.

EXAMPLE 106 N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-(4-fluorobenzoyl)piperidide Step 106a.N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine

To a suspension of serine(β-O-benzyl)-OH trifluoroacetate salt (2.0 g,6.47 mmol) in CH₂ Cl₂ (10 mL) and 5 mL of DMF were added NEt₃ (1 mL,7.00 mmol), 4-(N,N-dimethylamino)pyridine (855 mg, 7.00 mmol) andm-toluyl isocyanate (0.9 mL, 7.00 mmol). The mixture was stirredovernight at ambient temperature, then diluted with EtOAc and washedwith saturated aqueous KHSO₄, H₂ O, and brine, then dried (Na₂ SO₄) andevaporated to 2.5 g of crude product. Chromatography (silica, 2:1EtOAc/hexane with 3% HOAc) afforded 1.91 g (68%) of the title compound.MS (CI) m/e 329 (M+H)⁺. ¹ H NMR (DMSO-d₆, 300 MHz) δ: 2.22 (s, 3H); 3.68(q, 1H, J=4.5 Hz); 3.85 (q, 1H, J=4.5 Hz); 4.85 (m, 1H); 4.52 (d, 2H, J=3 Hz); 6.52 (d, 1H, J=9 Hz); 6.72 (d, 1H, J=9 Hz); 7.15 (m, 3H); 7.22(s, 1H); 7.35 (m, 5H); 8.78 (s,1H).

Step 106b.N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-4-fluorobenzoyl)piperidide

The product of example 106a was coupled to 4-(p-fluorobenzoyl)piperidineusing the EDCI/HOBt procedure in 1:1 DMF/CH₂ Cl₂ analogous to thatdescribed in example 94a. MS (CI) m/e 518 (M+H)⁺. ¹ H NMR (DMSO-d₆, 300MHz) δ: 1.35-1.45 (nt, 3H); 1.75-1.80 (m, 3H); 2.22 (s, 3H); 2.82 (m,1H); 3.55 (s, 2H); 3.70 m, 1H); 4.02 (m, 1H); 4.40 (m, 1H); 4.50 (d, 2H,J=6 Hz); 4.92 (m, 1H); 6.60 (d, 1H, J=9 Hz); 6.70 (d, 1H, J=9 Hz); 7.10(m, 2H, J=9 Hz); 7.20 (s, 1H); 7.30 (m, 6H); 8.06 (q, 2H, J=6 Hz); 8.75(m, 1H). C, H, N analysis calculated for C₃₀ H₃₂ FN₃ O₄.0.5 HOAc: C,67.99; H, 6.26; N, 7.67. Found: C, 67.90; H, 6.17; N, 7.73.

EXAMPLE 107N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-Serine-piperidine-4'-anilideStep 107a.N-(t-Butyloxycarbonyl)-(β-O-benzyl)-R-serine-4'-methoxycarbonylpiperidide

Methyl isonipecotate hydrochloride (Carr, et al., J. Org Chem. 55, 1399,1990) was coupled to N-(t-butyloxycarbonyl)-(β-O-benzyl)-R-serine usingthe procedure of example 94a. MS(CI) m/e 421 (M+H)⁺. NMR (CDCl₃,300 MHz)δ: 1.37-1.75 (m,11H, includes 1.43 (s,9H)), 1.77-1.97 (m,2H), 2.5 (m,1H), 2.75-3.16 (m,2H), 3.48-3.64 (m,2H), 3.67 (s,3H), 3.9 (m,1H), 4.35(m,1H), 4.50 (dd,J=10.5,21 Hz,2H), 4.85 (dd,J=6,12 Hz, 1H), 5.51 (d,J=9Hz, 1H), 7.25-7.45 (m,5H).

Step 107b.N-(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-4'-methoxycarbonylpiperidide.

The title compound was prepared from the product of example 107a usingthe procedure of example 94b. MS(CI) m/e 454 (M+H)⁺. NMR (CDCl₃,300 MHz)δ: 1.44-1.30 (m,2H), 1.31-1.98 (m,2H), 2.29 (s, 3H), 2.52 (m, 1H), 2.38(m,0.66H), 2.98-3.24 (m, 1.33H), 3.51-3.66 (m,2H), 3.68 (s,3H), 3.96(m,1H), 4.28 (m,0.SH), 4.40-4.48 (m,2.SH, includes 4.45 (s,2H)), 5.21(m, 1H), 6.55 (br s,1H), 6.83 (d,J=6 Hz, 1H), 7.12 (m, 1H), 7.16 (m,1H), 7.17-7.30 (m,6H), 7.44 (d,J=14 Hz, 1H). C, H, N analysis calculatedfor C₂₅ H₃₁ N₃ O₅ : C 66.21, H 6.89, N 9.26; found: C 66.06, H 6.59, N9.04.

Step 107c.(m-Toluylaminocarbonyl)-(β-O-benzyl)-R-serine-piperidine-4'-anilide.

The product of example 107b (5.7 g, 12.6 mmol) was dissolved in 32 mLmethanol and 6.3 mL of 2N aqueous NaOH. After 8 h the volatilecomponents were removed in vacuo, ethyl acetate and aqueous saturatedKHSO₄ were added and the aqueous layer was extracted three times. Thecombined organic extracts were washed with brine, dried over Na₂ SO₄,filtered and the volatile components evaporated. Fractions judged to bepure after silica gel chromatography, eluting first with ethylacetate:hexane (1:1) then with ethyl acetate:acetic acid (97:3), werepooled, and the volatile components were evaporated to give(m-toluylaminocarbonyl)-(β-O-benzyl)-R-serine-piperidine-4'-carboxylicacid as a white solid (4.1 g, 9.3 mmol) in 74% yield. The carboxylicacid (2.0 g, 4.5 mmol), aniline (0.4 g, 4.5 mmol), and NMM (0.5 g, 5.0mmol) were dissolved in CH₂ Cl₂ and cooled to ice bath temperature. EDCI(1.0 g, 5.0 mmol) addition and extractive work-up were carried out asdescribed in example 94a to give the crude title compound (2.3 g, 4.5mmol) in quantitative yield. A portion (121 mg, 0.24 mmol) was subjectedto silica gel chromatography in a manner similar to that described forexample 94a, eluting with ethyl acetate: hexane (2:1) to give the titlecompound as a white powder (83 mg, 0.16 mmol) in 67% yield. MS(CI) m/e515 (M+H)⁺. NMR (CDCl₃,300 MHz) δ: 1.56-1.83 (m,2H), 1.83-2.99 (m,2H),2.28 (s,3H), 2.46 (m,1H), 2.84 (m,1H), 3.13 (m,1H), 3.55-3.70 (m,2H),4.13 (br d,J=13.5 Hz,1H), 4.48 (s,2H), 4.57 (m, 1H), 5.20 (m, 1H), 6.42(br, 1H), 6.84 (d,J=7.5 Hz, 1H), 7.05- 7.23 (m,5H). 7.23-7.43 (m,8H),7.48 (d,J=7.5 Hz,2H). C, H, N analysis calculated for C₃₀ H₃₄ N₄ O₄ : C70.02, H 6.66, N 10.89; found: C 69.82, H 6.78, N 10.73.

EXAMPLE 108N-(m-Toluylaminocarbonyl)-(γ-pyrrolidin-1-yl)R-Glutamyl-piperidine-4'-anilide.Step 108a. N-(t-Butyloxycarbonyl)-isonipecotanilide.

Isonipecotic acid (2.0 g, 15 mmol), di-tert-butyl dicarbonate (6.76 g,30 mmol), and triethylamine (12 ml, 90 mmol) were dissolved in 10 ml of1,4-dioxane and 10 ml of water. The mixture was stirred for 24 hours atambient temperature, then diluted with EtoAc and washed with saturatedaqueous KHSO₄, and brine, dried over Na₂ SO₄, and evaporated to 3.3 g ofN-(t-Butyloxycarbonyl)-isonipecotic acid. TheN-(t-butyloxycarbonyl)-isonipecotic acid was coupled to aniline by theprocedure of example 94a to afford 431 mg of the title product. MS (CI)m/e 305 (M+H)⁺. 1HNMR (CDCl₃, 300 MHz) δ: 1.45 (s, 9H); 1.55 (m, 1H);1.65-1.72 (m, 2H); 1.82-1.96 (m, 2H); 2.38 (m, 1H); 2.80 (t, 2H); 4.2(m, 2H); 7.12-7.55 (m, 5H).

Step 108b.N-(t-Butyloxycarbonyl)-(γ-O-benzyl)-R-Glutamyl-piperidine-4'-anilide.

The product of example 108a (430 me, 1.41 mmol) was treated with 2 ml of45% trifluoroacetic acid (TFA) in CH₂ Cl₂ for approximately 2 hr, thenthe solution was concentrated in vacuo, and CH₂ Cl₂ was added andevaporated several times. The resulting piperidine-4'-anilidetrifluoroacetate was coupled toN-(t-Butyloxycarbonyl)-(γ-O-benzyl)-R-Glutamic acid using the procedureof example 94a to afford the title compound. MS (CI) m/e 524 (M+H)⁺. ¹HNMR (DMSO-d₆, 300 MHz) δ: 0.85 (m, 1H), 1.3 (m, 1H), 1.39 (s, 9H),1.75-1.90 (br, 4H), 2.45 (m, 2H), 2.65 (m, 2H), 4.05 (m, 2H), 4.45 (m,2H), 5.10 (s, 2H), 7.05 (m, 1H), 7.25-7.35 (m, 7H), 7.60 (br, d, 2H).

Step 108 c.N-(m-Toluylaminocarbonyl)-(γ-O-benzyl)-R-Glutamyl-piperidine-4'-anilide.

The product of example 108b was converted to the title compound usingthe procedure of example 94b. MS (CI) m/e 557 (M+H)⁺. ¹ HNMR (DMSO-d₆,300 MHz) δ: 1.45-1.72 (m, 2H), 1.80-1.98 (m, 4H), 2.24 (s, 3H), 2.45(br, d, 2H), 2.55-2.75 (m, 3H), 3.1 (m, 1H), 4.12 (br, d, 1H), 4.40 (br,d, 1H), 4.78 (m, 1H), 5.08 (s, 2H), 6.45 (t, 1H), 6.74 (d, 1H),6.95-7.15 (m, 4H), 7.20 (s, 1H), 7.25-7.7.36 (m, 5H), 7.58 (m, 2H), 8.62(d, 1H), 9.88 (d, 1H).

Step 108d. N-(m-Toluylaminocarbonyl)-(γ-pyrrolidin-1-yl-)-R-Glutamyl-piperidine-4'-anilide.

A solution of the product of example 108c (200 mg, 0.359 mmol) in DMF(10 ml) was hydrogenated under one atmosphere of hydrogen at ambienttemperature in the presence of 10% Pd/C (200 mg) for 4 hrs. The catalystwas removed by filtration and the filtrate was concerntrated in vacuo.The residue was triturated with ether to yield 180.3 mg of theN-(m-Toluylaminocarbonyl)-R-Glutamyl-piperidine-4'-anilide. TheN-(m-Toluylaminocarbonyl)-R-Glutamyl-piperidine-4'-anilide was coupledto pyrrolidine using the EDCI/HOBt procedure in 1:1 CH₂ Cl₂ /DMFanalogous to that described in example 94a, and afforded 50 mg of thetitle compound. MS (CI) m/e 520 (M+H)⁺. ¹ HNMR (DMSO-d₆, 300 MHz) δ:1.65 (s, 16H), 1.75 (t, 1H, J=6 Hz), 1.85 (m, 4H), 2.25 (s, 3H), 4.25(m, 1H), 4.75 (m, 1H): 6.72 (d, 1H, J= 7.5 Hz), 7.05 (q, 2H, J=7.5 Hz),7.18 (d, 1H, J=9 Hz), 7.38 (m, 3H), 7.62 (d, 2H, J=9 Hz), 9.18 (m, 1H),10.0 (s, 1H). C, H, N analysis calculated for C₂₉ H₃₇ N₅ O₄ : C, 67.03;H, 7.77; N, 13.47. Found: C, 67.21; H, 7.06; N, 13.52.

EXAMPLE 109N-(m-Toluylaminocarbonyl)-(β-O-pyrrolidinecarbamoyl)-R-Serine-piperidine-4'-anilide.Step 109a. N-(t-Butyloxycarbonyl)-R-serine-piperidine-4'-anilide.

The title compound is synthesized in a fashion analogous to thatdescribed in example 108b, using N-(t-butyloxycarbonyl)-R-serine inplace of N-(t-butyloxycarbonyl)-(γ-O-benzyl)-R-glutamate. ¹ H-NMR(CDCl₃, 300 MHz) δ: 1.36 (s, 9H), 1.42-1.89 (m, 5H), 2.59 (m, 1H), 3.07(m, 1H), 3.41 (m, 1H), 3.52 (m, 1H), 4.06 (m, 1H), 4.41 (rn, 2H),4.60-4.83 (m, 1H), 6.60-6.85 (m, 1H), 7.0 (m, 1H), 7.27 (t, J=7.5 Hz,H), 7.59 (d, J=7.5 Hz, 2H). MS (CI) m/e 392 (M+H)⁺.

Step 109b. N-(m-Toluylaminocarbonyl)-R-serine-piperidine-4'-anilide,

The product of example 109a was convened to the title compound using aprocedure analogous to that of example 94b. ¹ H-NMR (CDCl₃, 300 MHz) δ:1.70-2.24 (m, 5H, obscured), 2.26 (s, 3H), 2.65 (m, 1H), 2.81 (m, 1H),3.31 (m, 1H), 4.39 (m, 2H), 4.57 (m, 1H), 4.69 (m, 1H}, 5.37 (m, 1H),6.76-7.75 (m, 11H). MS (CI) m/e 425 (M+H)⁺.

Step 109c.N-(m-Toluylaminocarbonyl)-(β-O-pyrrolidinecarbamoyl)-R-serine-piperidine-4'-anilide.

To a solution of N-(t-Butyloxycarbonyl)-R-serine-piperidine-4'-anilide(105 mg, 0.247 mmol) in 1 ml of CH₂ Cl₂ were added pyrrolidinecarbonylchloride (99 mg 0.742 mmol), NEt₃ (0.043 nil, 0.309 mmol), and DMAP (38mg, 0.309 mmol) and the mixture was allowed to stand at ambienttemperature overnight. After 24 h of reaction, addtionalpyrrolidinecarbonyl chloride (99 mg) was added. After 48 h, the mixturewas subjected to standard acid-base workurn The crude product waschromatographed (silica gel, EtOAc) and the volatile components wereevaporated to give the title compound as a white solid (20 mg) in 16%yield. ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.82 (s, 5H), 1.90-2.29 (m, 4H), 2.30(s, 3H), 2.57 (m, 1H), 2.76 (m, 1H), 3.35 (m, 5H), 4.17-4.36 (m, 3H),4.57 (m, 1H), 5.21 (m, 1H), 6.13 1H), 6.83-7.61 m, 10H). MS (CI) m/e 522(M+H)⁺. CHN analysis calculated for: C₂₈ H₃₅ N₅ OS: C, 63.10, H, 6.91,N, 12.77; found: C, 63.10, H, 6.78, N, 12.69.

EXAMPLE 110N-(m-Toluylaminocarbonyl)-(β-O-benzylcarbamoyl)-R-serine-piperidine-4'-anilide.

The product of example 107b (2.14 g, 4.16 mmol) in ethanol/acetic acidwas stirred under a hydrogen atmosphere in the presence of 10% Pd/C for2 days. The catalyst was removed by filtration and the solvents wereevaporated. A solution of the resulting alcohol (120 mg, 0.28 mmol) inDMF (1 mL) was treated with benzyl isocyanate (0.105 mL, 0.849 mmol) andthe mixture was allowed to stir at room temperature for 3 days.Following standard acid-base work-up, the crude product was purified bychromatography (silica gel, 18:5:2 EtOAc:hexane:HOAc) to give the titlecompound as a white solid (88 mg) in 56% yield, m.p. 109°-112° C. ¹H-NMR (CDCl₃, 300 MHz) δ: 1.62-2.13 (m, 5H), 2.30 (s, 3H), 2.60 (m, 1H),2.76 (m, 1H), 3.28 (m, 1H), 4.15-4.36 (m, 4H), 4.57 (m, 2H), 5.28 (m,1H), 6.30 (m, 1H), 6.75-7.60 (m, 15H). MS (CI) m/e 558 (M+H)⁺. CHNanalysis calculated for: C₃₁ H₃₅ N₅ O₅. 0.40 AcOH: C, 65.66, H, 6.34, N,12.04; found: C, 65.53, H, 6.37, N, 11.96.

EXAMPLE 111N-(m-Toluylaminocarbonyl)-(β-O-(N,N-dimethylaminocarbamoyl)-R-serine-piperidine-4'-anilide.

N-(m-Toluylaminocarbonyl)-R-serine-piperidine-4'-anilide, obtained asdescribed in example 111,(93 mg, 0.219 mmol) in 1 ml of anhydrous CH₂Cl₂ was treated with NEt₃ (0.039 ml, 0.274 mmol), DMAP (34 mg, 0.274mmol), and N,N-dimethylaminocarbamoyl chloride (0.052 mL, 0.548 mmol)and the mixture was allowed to stand at ambient temperature overnight.After 24 h of reacticn, addtional N,N-dimethylaminocarbonyl chloride(0.052 mL) added. After 48 h, the mixture was subjected to standardacid-base workup. The crude product was chromatographed (silica gel,EtOAc) and the volatile components were evaporated to give the titlecompound as a white solid (52 mg) in 48% yield, m.p. 113°-1150° C. ¹H-NMR (CDCl₃, 300 MHz) δ: 1.70-2.20 (m, 5H), 2.30 (s, 3H), 2.58 (m, 1H),2.78 (m, 1H, obscured), 2.90 (s, 6H), 3.23 (m, lit), 4.27 (m, 2H), 4.45(m, 1H), 4.57 (m, 1H), 5.20 (m, 1H), 6.20 (m, 1H), 6.81-7.60 (m, 10H).MS (CI) m/e 496 (M+H)⁺. CHN analysis calculated for: C₂₆ H₃₃ N₅ O₅. 0.20H₂ O: C, 62.56, H, 6.74, N, 14.03; found: C, 62.48, H, 6.72, N, 13.98.

EXAMPLE 112N-(m-Toluylaminocarbonyl)-(β-O-(N,N-diethylaminocarbamoyl))-R-Serine-piperidine-4'-anilide.

The title compound was prepared in 38% yield as described for example111 substituting N,N-diethylaminocarbonyl chloride forN,N-dimethylaminocarbonyl chloride. m.p. 107°-110° C. ¹ H-NMR (CDCl₃,300 MHz) 6:1.09 (t, J=7.5 Hz, 6H), 1.62-2.20 (m, 5H), 2.33 (s., 3H),2.58 (m, 1H), 2.78 (m, 1H), 3.26 (br s, 6H), 4.10-4.34 (m, 3H), 4.54 (m,1H), 5.21 (m, 1H), 6.05 (m, 1H), 6.82-7.62 (m, 10H). MS (CI) m/e 524(M+H)⁺. CHN analysis calculated for: C₂₈ H₃₇ N₅ O₅.0.20 EtOAc: C, 63.91,H, 7.19 N, 12.94; found: C, 63.89, H, 7.13, N, 13.03.

EXAMPLE 113N,(m-Toluylaminocarbonyl)-(β-O-pyrrolidinecarbamoyl)-R-Serine-4'-benzoylpiperidideStep 113a. N-(t-Butyloxycarbonyl)-R-serine-4'-benzoylpiperidide

The title compound was prepared from N-(t-Butyloxycarbonyl)-R-serine and4-benzoylpiperidine using the procedure of example 94a.¹ H-NMR (CDCl₃300 MHz) δ: 1.45 (s, 9H), 1.61-2.02 (m, 4H). 2.80-3.05 (m, 1H), 3.25 (m,1H), 3.55 (m, 1H), 3.73 (m, 1H), 3.82 (m, 1H), 4.12 m, 1H), 4.40-4.71(m, 2H), 5.69 m, 1H), 7.46-7.63 (m, 3E), 7.95 (d, J=9 Hz, 2H). MS (CI)m/e 377 (M+H)⁺.

Step 113b. N-(m-Toluylaminocarbonyl)-R-serine-4'-benzoylpiperidide

The product of example 113a was converted to the title compound usingthe procedure of example 94b. ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.65-2.01 (m,4H), 2.30 (s, 3H), 2.99 (m, 1H), 3.32 (m, 1H), 3.55 (m, 1H), 3.83 (m,2H), 4.15 (m, 1H, obscured), 4.51 (m, 1H), 4.99 (m, 1H), 6.39 (m, 1H),6.86 (d, J=9 Hz, 1H), 7.14 (m, 4H), 7.43-7.65 (m. 3H), 7.92 (d, J=9 Hz,2H). MS (CI) m/e 410 (M+H)⁺.

Step 113c.N-(m-Toluylaminocarbonyl)-(β-O-pyrrolidinecarbamoyl)-R-serine-4'-benzoylpiperidide

The product of example 113b was converted to the title compound using aprocedure analogous to that of example 109c. m.p. 101°-103° C., ¹ H-NMR(CDCl₃, 300 MHz) δ: 1.64-2.11 (m, 8H), 2.30 (s, 3I-D, 2.99 (m, 1H), 3.34(m, 5H), 3.53 (m, 1H), 4.18-4.56 (m, 4H), 5.26 (ra, 1H), 6.19 (m, 1H),6.86 (d, J=9 Hz, 1H), 6.99 (d, J=10.5 Hz, 1H), 7.15 (m, 3H), 7.49 (m,2H), 7.58 (m, 1H), 7.92 (d, J=9 Hz, 2H). MS (CI) m/e 507 (M+H)⁺. CHNanalysis calculated for: C₂₈ H₃₄ N₄ O₅. 0.30 H₂ O: C, 65.68, H, 6.81, N,10.94; found: C, 65.65, H, 6.66, N, 10.68.

EXAMPLE 114N-(m-Toluylaminocarbonyl)-(β-O-morpholinecarbamoyl)-R-Serine-4'-benzoylpiperidide

The product of example 113b was converted to the title compound using aprocedure analogous to that of example 109c, using morpholinecarbamoylchloride in place of pyrrolidinecarbamoyl chloride. m.p. 104°-106° C. ¹H-NMR (CDCl₃, 300 MHz) δ: 1.60-2.11 (m, 5H), 2.30 (s, 3H), 3.0 (m, 2H),3.44 (s, 4H), 3.61 (s, 4H), 4.04-4.56 (m, 4H), 5.28 (m, 1H), 6.16 (m,1H), 6.88 (m, 2H), 7.15 (m, 3H), 7.49 (m, 2H), 7.58 (m, 1H), 7.92 (m,2H). MS (CI) m/e 523 (M+H)⁺. CHN analysis calculated for: C₂₈ H₃₄ N₄O₆.0.20 H₂ O: C, 63.91, H, 6.59, N, 10.65; found: C, 64.01, H, 6.51, N,10.55.

EXAMPLE 115N-(m-Toluylaminocarbonyl)-(β-O-anilinecarbamoyl)-R-serine-4'-benzoylpiperidideStep 115a. N-(t-Butyloxycarbonyl)-(β-O-phenylaminocarbamoyl)-R-serine.

N-(t-Butyloxycarbonyl)-R-serine (1.4 g, 6.82 mmol), in 5 ml of anhydrousDMF was treated with phenyl isocyanate (1.48 ml, 13.65 mmol) and themixture was allowed to stand at ambient temperature overnight. After 24h of reaction, saturated aqueous NaHCO₃ was added. The aqueous portionwas extracted three times with ethyl acetate, then the aqueous phase wasacidified with solid KHSO₄ and further extracted with EtOAc. Thecombined organic extracts were washed with brine, dried over Na₂ SO₄,then concentrated to give the title compound as a pale yellow solid(2.3g). ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.47 (s, 9H), 4.55 (m, 2H), 4.60 (m,1H), 5.47 (m, 1H), 7.07 (m, 1H), 7.24-7.42 (m, 5H). MS (CI) m/e 342(M+NH4)⁺.

Step 115b,N-(t-Butyloxycarbonyl)-(β-O-phenylaminocarbamoyl)-R-serine-4'-benzoylpiperidide.

The product of example 115a (300 mg, 0.925 mmol), 4-benzoylpiperidinehydrochloride (251 mg, 1.11 mmol), and N-methylmorpholine (NMM) (0.195ml, 2.78 mmol) were dissolved in 10 ml of anhydrous CH₂ Cl₂ :DMF (1:1).The mixture was cooled to ice bath temperature and EDCI (213 mg, 1.11mmol) was added. The reaction was allowed to stir at ice bathtemperature for 2 h and then allowed to warm to ambient temperatureovernight. Standard acid-base work-up, followed by trituration of thecrude product with CH₂ Cl₂ afforded 201 mg (44%) of a fine white solid.m.p. 215°-216° C. ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.44 (s, 9H), 1.54 (s,2H), 1.97 (m, 3H), 2.94 (m, 1H), 3.35 (m, 1H), 3.59 (m, 1H), 4.07-4.61(m, 4H), 5.0 (m. 1H), 6.97-8.01 (m, 11H). MS (CI) m/e 496 (M+H)⁺.

Step 115c.N-(m-Toluylaminocarbonyl)-(β-O-phenylaminocarbamoyl)-R-serine-4'-benzoylpiperidide.

The product of example 115b was converted to the title compound usingthe procedure of example 94b. m.p. 108°-110° C. ¹ H-NMR (CDCl₃, 300 MHz)δ: 1.70-2.15 (m, 5H), 2.29 (s, 3H), 3.02 (m, 1H), 3.42 (m, 1H), 3.58 (m,1H), 4.09-4.62 (m, 4H), 5.32 (m, 1H), 6.80-8.0 (m, 16H). MS (CI)m/e 529(M+H)⁺. CHN analysis calculated for: C₃₀ H₃₂ N₄ O₅.0.30 EtOAc: C, 67.52,H, 6.25, N, 10.09; found: C, 67.44, H, 6.23, N, 10.09.

EXAMPLE 116 (m-Toluylaminocarbonyl)-(β-O-benzyl)-R-Serine-piperidine-4'-m-bromocarboxanilide.

The title compound was prepared from the product of example 107b by aprocedure analogous to example 107c, substituting m-bromoaniline foraniline.m.p. 111°-113° C, ¹ H-NMR (CDCl₃, 300 MHz) δ: 1.56-2.01 (m, 4H),2.30 (s, 3H), 2.45 (m, 1H), 2.85 (m, 1H), 3.13 (m, 1H), 3.60 (m, 1H),3.67 (m, 1H), 4.12 (m, 1H), 4.50 (s, 2H), 4.58 (rn, 1H), 5.18 (m, 1H),6.15 (d, J=9 Hz, 1H), 6.82-7.80 (m, 15H). MS (CI) m/e 595 (M+H)⁺. CHNanalysis calculated for: C₃₀ H₃₃ N₄ O₄ Br. 0.10 EtOAc: C, 60.62, H,5.66, N, 9.30; found: C, 60.41, H, 5.65, N, 934.

EXAMPLE 117N-(3'-Quinolylcarbonyl)-2-allyl-R,S-phenylalanine-n-pentylamide Step117a. N-(Trifluoroacetyl)-2-allyl-R,S-phenylalanine-n-pentylamide.

A solution of (R,S)-5-allyl-5-benzyl-2-trifluoromethyloxazol-4-one (ca.3.5 mmol), generated from N-trifluoroacetyl-R-phenylalanine allyl esteraccording to the literature procedure (Holladay and Nadzan, J. Org.Chem. 56, 3900, 1991), in THF (50 mL) was treated with N-pentylamine (2mL, 17 mmol), and the mixture was allowed to stand at ambienttemperature overnight. After standard acid-base work-up, the crudeproduct was chromatographed over silica gel to afford 1.47 g product,which was crystallized from Et2O/hexane to afford 969 mg (79%) ofcolorless crystals. ¹ HNMR (CDCl₃) δ: 0.9 (t, J=4 Hz, 3H), 1.32 (m, 4H),1.55 (m, 2H), 2.52 (dd, J=3, 9 Hz, 1H), 3.11 (d, J=9 Hz, 1H), 3.28 (m,1H), 3.36 (m, 1H), 3.42 (dd, J=4, 9 Hz), 3.67 (d, J=9 Hz, 1 H), 5.17 (m,2H), 5.59 (m, 1H), 5.72 (br t, 1H), 7.09 (m, 2H), 7.29 (m, 3H), 7.84 (s,1H).

Step 117b.N-(3'-Quinolylcarbonyl)-2-allyl-R,S-phenylalanine-n-pentylamide.

A solution of the product of Example 117a (280 mg, 0.76 mmol) in 10 mLof MeOH was treated with 10 mL of saturated aqueous Ba(OH)2 and heatedat 90° C. for 24h. The solvent was evaporated and the residue wasextracted twice with EtOAc. The organic fraction was washed with waterand brine, then dried (Na₂ SO₄) and concentrated to 201 mg of freeamine. A solution of the amine. quinoline-3-carboxylic acid (152 mg,0.87 mmol), 4-(N,N-dimethylamino)pyridine (106 mg, 0.87 mmol) and NEt₃(0.2 mL, 1.4 mmol) in CH₂ Cl₂ was treated with1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate(CMC, 368 mg, 0.87 mmol). After several days of reaction, additionalquinoline-3-carboxylic acid (152 mg) and CMC (368 mg) were added. Afterseveral more days, the mixture was subjected to standard acid-basework-up. The crude product was chromatographed (silica gel, 2:1hexane/EtOAc) then crystallized from CH₂ Cl₂ /hexane to afford 66 mg ofthe title compound, m.p. 157°-159° C. ¹ H-NMR (CDCl₃) δ: 0.92 (t, J=7Hz, 3H), 1.32 (m, 4H), 1.60 (m, 2H), 2.70 (dd, J=7, 15 Hz, 1H), 3.28 (d,J=15 Hz, 1H), 3.37 (m, 2H), 3.54 (dd, J=7.5, 9 Hz, 1H), 3.83 (d, J=15Hz, 1H),5.18 (m, 2H), 5.72 (m, 1H), 6.13 (br t, 1H), 7.12 (m, 2H), 7.21(m, 2H), 7.60 (m, 2H), 7.80 (m, m, 1H), 7.88 (d, J=8 Hz, 1H), 8.15 (d,J=8 Hz, 1H), 8.41 (d, J=2 Hz, 1H), 9.22 (d, J=2 Hz, 1HL MS (CI) m/e 430(M+H)⁺. Anal. Calcd for C₂₇ H₃₁ N₃ O₂.0.25 H₂ O: C, 74.74, H, 7.34, N,9.69. Found: C, 74.34, H, 7.44, N, 9.71.

EXAMPLE 118 1-n-pentyl-2-oxo-3-benzyl-3-quinoline-3'-carbonylaminopyrrolidine Step118a. 1-n-pentyl-2-oxo-3-benzyl-3-trifluoroacetylaminopyrrolidine.

The product of Example 117a (20 mg, 0.54 mmol), and 4-methylmorpholineN-oxide monohydrate (NMMO.H₂ O) (81 mg, 0.60 mmol) were dissolved inacetonitrile (8.6 mL) and H₂ O (4.3 mL) at ambient temperature. Osmiumtetraoxide (OsO₄) (0.072 mL, 0.006 mmol) and sodium periodate (NaIO₄)(462 mg, 2.16 mmol) were added sequentially and the mixture was stirredfor 48 h whereupon H₂ O (10 mL) was added and residual OsO₄ and CH₃ CNremoved in vacuo. Ethyl acetate was added, and extractive work-up wasperformed as described in example 94a to give a clear oil which was thendissolved in anhydrous CH₂ Cl₂ (2 mL) under nitrogen atmosphere andtreated with triethylsilane (0.173 mL, 1.1 mmol), followed bytrifluoroacetic acid (0.21 mL, 2.7 mmol). After 2 h the volatilecomponents were removed in vacuo, ethyl acetate was added, and theorganic layer was washed twice with 10% aqueous Na₂ CO₃ and twice withbrine. The solution was dried, filtered, evaporated and the residuesubjected to silica gel purification eluting with hexane:ethylacetate:acetic acid (60:10:2) as in example 94a to give the titlecompound (145 mg, 0.41 mmol) in 76% yield. MS(CI) m/e 357 (M+H)⁺, 374(M+NH₄)⁺. NMR (CDCl₃,300 MHz) δ: 0.88 (t,J=7.5 Hz,3H), 1.12-1.42 (m,6H),2.17-2.36 (m,2H), 2.77 (m, 1H), 2.97-3.26 (m,5H), 7.03 (s,1H), 7.18-7,23(m,2H), 7.25-7.32 (m,3H).

Step 118b.1-n-pentyl-2-oxo-3-benzyl-3-quinoline-3'-carbonylaminopyrrolidine

The product example 118a (127 mg, 0.36 mmol) was combined with methanol(5 mL) and aqueous saturated Ba(OH)2 (4 mL) and allowed to stirovernight at ambient temperature whereupon the volatile components wereremoved in vacuo. CHCl₃ and brine were added and the aqueous layer wasextracted four times with CHCl₃, and the combined organic extracts weredried with Na₂ SO₄, filtered, and the volatile components wereevaporated. The resulting 1-n-pentyl-2-oxo-3-benzyl-3-aminopyrrolidine(94 mg) was then coupled to 3-quinoline-3-carboxylic acid (62 mg, 0.36mmol) using HOBt (61 mg, 0.40 mmol) and EDCI (77 mg, 0.40 mmol) in amanner similar to that described for example 94a substitutingdiisopropylethylamine (NEtiPr₂) (2 drops) for NMM. The reactionproceeded slowly for 12 days at ambient temperature and additional EDCI(0.12 mmol), HOBt (0.12 mmol), NEtiPr2 (7-9 mmol) andN,N-dimethylaminopyridine (DMAP) (0.07 mmol) were added to the reactionduring this time. Extractive work-up was carried out as described inexample 94a and the crude product was subjected to radial thin layerchromatography eluting with ethyl acetate:hexane:acetic acid (16:16:1)followed by two successive recrystallizations from ethanol/hexane togive the title compound (90 mg, 0.22 mmol) in 60% yield. MS(CI) m/e 415(M+H)⁺. NMR (CDCl₃,300 MHz) δ: 0.9 (t,J=7.5 Hz,3H), 1.17-1.45 (m,6H),2.35 (m, 1H), 2.52 (m, 1H), 2.92 (m, 1H), 3.05-3.29 (m,3H), 3.42(s,0.66H), 3.47 (s,0.33H), 3.5 (br s, 1H), 7.07 (s, 1H), 7.27 (s,5H),7.63 (m,1H), 7.84 (m,1H), 7.92 (dd,J=l.5,7.5 Hz, 1H), 8.28 (d,J=8.4 Hz,1H), 8.55 (d,J=l.8 Hz, 1H), 9.32 (d,J=2.5 Hz, 1H). C, H, N analysiscalculated for C₂₆ H₂₉ N₃ O₂, 1.5 H₂ O: C 70.56, H 7.29, N 9.49; found:C 70.55, H 6.78, N 9.44.

The ability of the compounds of Formula I to interact with CCK receptorsand to antagonize CCK can be demonstrated in vitro using the followingprotocols.

Pharmacological Methods

CCK₈ [Asp-Tyr(SO₃ H)-Met-Gly-Trp-Met-Asp-Phe-NH2] was purchased fromPeptide International (Louisville, Ky.) or Cambridge ResearchBiochemicals (Atlantic Beach, N.Y.) EGTA, HEPES and BSA were purchasedfrom Sigma Chemical Co. (St. Louis, Mo.). [¹²⁵ I]BH-CCK.sub.₈ (specificactivity, 2200 Ci/mmol) and Aquasol-2 scintillation cocktail wereobtained from New England Nuclear (Boston, Mass.). Bestatin andphosphoramidon were purchased from Peptide International. Male guineapigs, 250 to 325 g, were obtained from Scientific Small AnimalLaboratory and Farm (Arlington Heights, Ill.).

Protocol for Radioligand Binding Experiments

1. Guinea Pig Cerebral Cortical and Pancreatic Membrane Preparations

Cortical and pancreatic membranes were prepared as described (Lin andMiller; J. Pharmacol. Exp. Ther. 232, 775-780, 1985). In brief, cortexand pancreas were removed and rinsed with ice-cold saline. Visible fatand connective tissues were removed from the pancreas. Tissues wereweighed and homogenized separately in approximately 25 mL of ice-cold 50mM Tris-HCl buffer, pH 7.4 at 4° C., with a Brinkman Poloytron for 30sec, setting 7. The homogenates were centrifuged for 10 min at 1075×gand pellets discarded. The supernatants were saved and centrifuged at38,730×g for 20 min. The resultant pellets were rehomogenized in 25 mLof 50 mM Tris-HCl buffer with Teflon-glass homogenizer, 5 up and downstrokes. The homogenates were centrifuged again at 38,730×g for 20 min.Pellets were then resuspended in 20 mM HEPES, containing 1 mM EGTA, 118mM NaCl, 4.7 mM KCl, 5 mM MgCl₂, 100 μM bestatin, 3 μM phosphoramidon,pH 7.4 at 22° C., with a Teflon-glass homogenizer, 15 up and downstrokes. Resuspension volume was 15-18 mL per gram of original wetweight for the cortex and 60 mL per gram for the pancreas.

Incubation Conditions

[¹²⁵ I]Bolton-Hunter CCK₈ ([¹²⁵ I]BH-CCK₈), and the test compounds werediluted with HEPES-EGTA-salt buffer (see above) containing 0.5% bovineserum albumin (BSA). To 1 mL Skatron polystyrene tubes were added 25 μLof [.sup. 125 I]BH-CCK₈, and 200 μL of membrane suspension. The finalBSA concentration was 0.1%. The cortical tissues were incubated at 30°C. for 150 min and pancreatic; tissues were incubated at 37° C. for 30min. Incubations were terminated by filtration using Skatron CellHarvester and SS32 microfiber filter mats. The specific binding of [¹²⁵I]BH-CCK₈, defined as the difference between binding in the absence andpresence of 1 μM CCK₈, was 85-90% of total binding in cortex and 90-95%in pancreas. IC₅₀ 's were determined from the Hill analysis. The resultsof these binding assays are shown in Table 1.

Protocol for Amylase Release

This assay was performed using the modified protocol of Lin et al., J.Pharmacol. Exp. Ther. 236, 729-734, 1986.

1. Guinea Pig Acini Preparation

Guinea pig acini were prepared by the method of Bruzzone et al.(Biochem. J. 226, 621-624, 1985) as follows. The pancreas was dissectedand connective tissues and blood vessels were removed. The pancreas wascut into small pieces (2 mm) by a seizure and placed in a 15 mL conicalplastic tube containing 2.5 mL of Krebs-Ringer HEPES (KRH) buffer plus400 units per mL of collagenase. The composition of the KRH buffer was:HEPES, 12.5 mM; NaCl, 118 mM; KCl, 4.8 mM; CaCI₂, mM; KH₂ PO₄, 1.2 mM;MgSO₄, 1.2 mM; NaHCO₃, 5 mM; glucose, 10 mM at pH 7.4. The buffer wassupplemented with 1% MEM vitamins, 1% MEM amino acids and 0.001%aprotinin. The tube was shaken by hand until the suspension appearedhomogeneous, usually 5-6 min. Five mL of the KRH, without collagenaseand with 0.1% BSA, was added and the tube was centrifuged at 50×g for 35sec. The supernatant was discarded and 6 mL of the KRH was added to thecell pellet. Cells were triturated by a glass pipette and centrifuged at50×g for 35 sec. This wash procedure was repeated once. The cell pelletfrom the last centrifugation step was then resuspended in 15 mL of KRHcontaining 0.1% BSA. The contents were filtered through a dual nylonmesh, size 275 and 75 μM. The tiltrate, containing the acini, wascentrifuged at 50×g for 3 min. The acini were then resuspended in 5 mLof KRH-BSA buffer for 30 min at 37° C., under 100% oxygen atmosphere(O₂), with a change of fresh buffer at 15 min.

2. Amylase Assay

After the 30 min incubation time, the acini were resuspended in 100volumes of KRH-BSA buffer, containing 3 μM phosphoramidon and 100 μMbestatin. While stirring, 400 μL of acini were added to 1.5 mLmicrocentrifuge tubes containing 50 μL of CCK₈, buffer, or testcompounds. The final assay volume was 500 μL. Tubes were vortexed andplaced in a 37° C. water bath, under 100% O₂, for 30 min. Afterward,tubes were centrifuged at 10,000 g for 1 min. Amylase activity in thesupernatant and the cell pellet were separately determined afterappropriate dilutions in 0.1% Triton X-100, 10 mM NaH₂ PO₄, pH 7.4 byAbbott Amylase A-gent test using the Abbott Bichromatic Analyzer 200.The reference concentration for CCK₈ in determining the IC₅₀ 's of thecompounds of Formula I was 3×10⁻¹⁰ M. The results of this assay areshown in Table 2. These results indicate that compounds of the inventionare CCK antagonists.

In Vitro Results

The preferred compounds of Formula I are those which inhibited specific[¹²⁵ I]-BH-CCK₈ binding in a concentration dependent manner. Analysis of[¹²⁵ I]-BH-CCK₈ receptor binding in the absence and presence of thecompounds of formula I indicated the compounds of formula I inhibitedspecific [¹²⁵ I]-BH-CCK₈ receptor binding. The IC₅₀ values of thecompounds of Formula I are presented in Table 1.

                  TABLE 1                                                         ______________________________________                                        [.sup.125 I]-BH-CCK.sub.8 Binding                                             Compound of    Pancreas  Cortex                                               Example        IC.sub.50 (nM)                                                                          IC.sub.50 (nM)                                       ______________________________________                                         1             40        17,000                                                2             100       >10,000                                               3             27        >10,000                                               4             290       >10,000                                               5             12        <10,000                                               6             1000      >10,000                                               7             8200      >10,000                                               8             4800      >10,000                                               9             190       1-10,000                                             10             1100      >10,000                                              11             200       ˜100,000                                       12             1300      55,000                                               13             1600      >10,000                                              14             4400      >10,000                                              15             87        ˜10,000                                        16             170       >10,000                                              17             140       7,200                                                18             170       ˜10,000                                        19             73        ˜10,000                                        20             23        ≧10,000                                       21             30        ˜10,000                                        22             9         >10,000                                              23             210       ˜10,000                                        24             1100      >10,000                                              25             48        1,400                                                26             24        ˜10,000                                        27             320       ˜10,000                                        28             1000      >10,000                                              29             19        2,400                                                30             960       >10,000                                              31             950       >10,000                                              32             41        <10,000                                              33             530       >10,000                                              35             140       5,200                                                36             150       1-10,000                                             37             1800      >10,000                                              38             260       ˜10,000                                        39             180       >10,000                                              40             70        ˜10,000                                        41             160       > 10,000                                             42             92        >10,000                                              43             1600      >10,000                                              44             37        ˜10,000                                        45             120       5,300                                                 46a           250       >30,000                                               46b           800       9,100                                                49             29        ≧10,000                                       51             120       3,000                                                52             145       ˜10,000                                        53             >10,000   >10,000                                              54             56        ˜10,000                                        55             63        ˜10,000                                        58             3100      >10,000                                              61             820       4,900                                                63             1300      >10,000                                              65             74        28,000                                               66             42        3,300                                                67             110       6,200                                                68             330       ˜10,000                                        69             640       >10,000                                              70             160       ˜10,000                                        71             83        >10,000                                              72             5500      >10,000                                              73             9.3       1,600                                                74             3.1       1,700                                                75             210       ˜10,000                                        76             870       ˜10,000                                        77             69        6,000                                                78             350       ˜10,000                                        79             1300      <100,000                                             80             2600      >10,000                                              81             160       >10,000                                              82             130       nd                                                   83             1-10,000  nd                                                   84             100       nd                                                   86             86        2,900                                                87             980       >10,000                                              88             51        nd                                                   89             520       >10,000                                              90             1090      >10,000                                              91             1000      >10,000                                              92             230       <10,000                                              93             60        5,300                                                94             2130      318                                                  95             950       270                                                  96             1610      53                                                   97             1750      61                                                   98             28        >10,000                                              99             1900      595                                                  100            2400      375                                                  101            2400      375                                                  102            nd        629                                                  103            1300      290                                                  104            951       400                                                  105            533       77                                                   106            350       190                                                  107            430       110                                                  108            1270      235                                                  109            272       22                                                   110            220       135                                                  111            318       552                                                  112            229       445                                                  113            1010      40                                                   114            nd        132                                                  115            208       115                                                  116            1280      728                                                  117            87        nd                                                   118            121       nd                                                   ______________________________________                                    

The results herein also indicate that compounds of the invention possessselectivity for the pancreatic (type A) CCK receptors.

                  TABLE 2                                                         ______________________________________                                        Inhibition of CCK-8-induced Amylase Release                                   Cmpd of                                                                       Example             IC.sub.50 (nM)                                            ______________________________________                                         1                  290                                                        2                  <100,000                                                   4                  <100,000                                                   5                  <10,000                                                    6                  <100,000                                                   7                  ˜100,000                                             8                  <100,000                                                   9                  <100,000                                                  10                  <100,000                                                  11                  <30,000                                                   12                  <100,000                                                  13                  <100,000                                                  14                  <100,000                                                  15                  <100,000                                                  16                  <100,000                                                  17                  <100,000                                                  18                  <100,000                                                  19                  <100,000                                                  20                  140                                                       21                  <100,000                                                  22                  <100,000                                                  24                  <10,000                                                   25                  140                                                       26                  <100,000                                                  27                  <100,000                                                  28                  ˜100,000                                            29                  <100,000                                                  30                  <100,000                                                  32                  <100,000                                                  33                  <100,000                                                  39                  <100,000                                                  40                  <100,000                                                  41                  <100,000                                                  42                  <100,000                                                  43                  >10,000*                                                  44                  <10,000                                                   45                  <10,000                                                    46a                <100,000                                                  51                  <10,000                                                   52                  <100,000                                                  54                  <10,000                                                   58                  <10,000                                                   65                  <1,000                                                    66                  <1,000                                                    70                  <100,000                                                  71                  <100,000                                                  72                  <100,000                                                  73                  <100,000                                                  74                  <100,000                                                  75                  <100,000                                                  77                  <100,000                                                  80                  <10,000                                                   88                  <1,000                                                    92                  <100,000                                                  93                  <10,000                                                   ______________________________________                                          *(37.5% inhibition)                                                     

Protocol for Calcium Release Assay

This protocol is as described in Lin, et al. Mol. Pharm. 36, 881-886,1989. NCI-H345 cells were cultured according to Yoder,and Moody,Peptides 8, 103-107, 1987, except that the medium was modified to RPMI1640 with 2.5% fetal bovine serum (heat inactivated), 5 mcg/L sodiumselenite, 5 mg/L human transferrin, 5 mg/L, insulin, 100 units/mLpenicillin and 100 μg/L streptomycin. Cells (ca. 200,000/mL) were loadedwith 1 mcM indo-1/AM for 1h, washed, and resuspended in Dulbeco'sphosphate buffered saline, pH 7.4, plus 0.1% BSA and 0.1% glucose.Intracellular Ca²⁺ levels were monitored with a SLM 8000Cspectrofluorimeter with settings of 350 nm excitation and 405 and 480 nmemissions. Calibrations of [Ca²⁺ ]i were done as described inGrynkiewicz, et al, J. Biol. Chem. 260, 3440-3450, 1985:

    [Ca.sup.2+ ].sub.i =K.sub.d (R-R.sub.min)/(R.sub.max -R)

where R_(min) and R_(max) were the ratios (480/405) obtained in thepresence of excess EGTA (10 mM) and digitonin (50 mcM), respectively.K_(d) is assumed to be 240 nM, and R is the ratio in the presence andthe absence of CCK. Basal calcium levels were 147±3 (n=3) and themaximum levels of calcium stimulated with 1 mcM CCK-8 were 357±3. Testcompounds were incubated in varying concentrations with the cells priorto addition of CCK-8 to a final concentration of 10 nM. The IC₅₀ valuerepresents the concentration that decreases the response elicited byCCK-8 by 50%.

Table 3 presents the data obtained in the calcium release assay forselected compounds of formula I. These data demonstrate that theactivity of these compounds is as antagonistic agents.

                  TABLE 3                                                         ______________________________________                                        Calcium Release Assay                                                         Compound of                                                                   Example No.    IC.sub.50 (nM)                                                 ______________________________________                                         96               251                                                         109               220                                                         113               115                                                         ______________________________________                                    

In Vivo Results

The ability of the compounds of Formula I to interact with CCK receptorsand to antagonize CCK in vivo can be demonstrated using the followingprotocols.

Inhibition of CCK Induced Gastric Emptying

Three fasted mice were dosed (p.o.) with the test compound. CCK₈ (80μg/kg s.c.) was administered within 60 minutes and charcoal meal (0.1 mLof 10% suspension) was given orally 5 minutes later. The animals weresacrificed within an additional 5 minutes.

Gastric emptying, defined as the presence of charcoal within theintestine beyond the pyloric sphincter, is inhibited by CCK₈. Gastricemptying observed in 2 or 3 mice (greater than 1) indicates antagonismof CCK₈.

    ______________________________________                                        Compound              Number of mice                                          of example  Dose (p.o.)                                                                             with Gastric Emptying                                   ______________________________________                                        66          100 mg/kg 2                                                       ______________________________________                                    

Measurement of Plasma Insulin Level Following Treatment with CCK₈ and aCompound of Formula I

The ability of the compounds of Formula I to antagonize CCK inducedhyperinsulinemia can be demonstrated in vivo using the followingprotocol.

Male mice, 20-30 g, were used in all experiments. The animals were fedwith laboratory lab chow and water ad libitum. The compound of Formula I(1-100 mg/kg in 0.2 mL of 0.9% saline) was administered i.p. Ten minuteslater CCK₈ (0,2 to 200 nmole/kg in 0,2 mL of 0,9% saline) or saline wasinjected into the tail vein. Two minutes later the animals weresacrificed and blood was collected into 1,5 mL heparinized polypropylenetubes, The tubes were centrifuged at 10,000×g for 2 minutes. Insulinlevels were determined in the supernatant (plasma) by an RIA methodusing kits from Radioassay Systems Laboratory (Carson, Calif.) or NovoBiolabs (Mass.).

Antagonism of CCK Mediated Behavioral Effect in Mice with Compounds ofFormula I

Male Swiss CD-1 mice (Charles River) (22-27 g) are provided ample food(Purina Lab Chow) and water until the time of their injection with thetest compounds.

ICV injections were given by a free-hand method similar to thatpreviously described (Haley and McCormick, Br, J. Pharmacol. Chemother.12, 12-15 1957). The animals were placed on a slightly elevated metalgrid and restrained by the thumb and forefinger at the level of theshoulders, thus immobilizing their heads. Injections were made with a 30gauge needle with a "stop" consisting of a piece of tygon tubing tolimit penetration of the needle to about 4.5 mm below the surface of theskin. The needle was inserted perpendicular to the skull at a midlinepoint equidistant from the eye and an equal distance posterior from thelevel of the eyes such that the injection site and the two eyes form anequilateral triangle. The injection volume (5 μL) was expelled smoothlyover a period of approximately 1 second.

Immediately after the injections the mice were placed in their cages andallowed a 15 minute recovery period prior to the beginning of thebehavioral observations.

For the behavioral observations, the mice were placed in clear plasticcages. Each cage measured 19×26×15 centimeters and contained a 60-tubepolypropylene test tube rack (NALGENE #5970-0020) placed on end in thecenter of the cage to enhance exploratory activity. Observations weremade every 30 seconds for a period of 30 minutes. Behavior was comparedbetween drug and CCK₈ treated mice; CCK₈ treated mice; and mice treatedwith an equal volume of carrier (usually 0.9% saline or 5%dimethylsulfoxide in water). Locomotion as reported here consisted ofeither floor locomotion or active climbing on the rack. Differencesamong groups were analyzed by Newman-Kewels analysis and a probabilitylevel of p< 0.05 was accepted as significant. Each group testedconsisted of 10 animals. The results of this test indicate thatcompounds of Formula I are antagonists of CCK in vivo. Minimallyeffective doses (MED) are defined as that dose at which a statisticallysignificant reversal of CCK-induced inactivity was observed when thetest compound of formula I and CCK₈ were coadministered.

    ______________________________________                                        Compound of     Dose of                                                       Example         CCK.sub.8                                                                              MED                                                  ______________________________________                                        25              3 nmol   3 nmol                                               ______________________________________                                    

Protocol for Plus-Maze AsSay,

Male CD1 mice from Charles River weighing 25-30 g were used. They werehoused in groups of 14 in Plexiglas cages and located in atemperature-regulated environment with lights on between 7:00 and 20:00h. All animals used were naive to the apparatus. The elevated plus-mazewas made of Plexiglas and consisted of two open arms (17×8.0 cm) and twoenclosed arms (17×8×15 cm) extending from a central platform (8×8cm)(Lister, Psychophartnacology 92: 180-185,1987). It was mounted on aPlexiglas base raised 39 cm above the floor. Light levels on the openand enclosed arms were similar. Animals received i.p. injections of thedrug 15 min before the beginning of the test. At the beginning of theexperiment, mice were placed in the center of the maze and the followingvariables scored: 1) the time spent in the open arms; 2) the totaldistance traveled by the mice. These variables were automaticallyrecorded by a camera mounted above the apparatus and analyzed bycomputer software (Videomex, Columbus Instruments, Columbus, Ohio). Thetest lasted 5 minutes.

                  TABLE 4                                                         ______________________________________                                        Anxiolytic-like effect of selected compounds upon                             elevated plus-maze behavior of mice.                                          Drug treatment Time in open arms                                              mg/kg          (sec)                                                          ______________________________________                                        Cmpd of Ex. 109                                                               0              46.8 ± 4.6                                                  0.001          54.1 ± 3.7                                                  0.01           51.9 ± 4.5                                                  0.1             71.5 ± 5.0*                                                1.0            54.6 ± 6.0                                                  Cmpd of Ex 113                                                                0              31.7 ± 8.1                                                  0.001           53.4 ± 4.9*                                                0.01           38.1 ± 7.1                                                  0.1            46.1 ± 5.5                                                  1.0            48.7 ± 5.9                                                  ______________________________________                                         *statistically significant difference from control                       

The compounds of Formula I antagonize CCK which makes the compoundsuseful in the treatment and prevention of disease states in mammals(especially humans) wherein CCK or gastrin may be involved, for example,gastrointestinal disorders such as irritable bowel syndrome, ulcers,excess pancreatic or gastric secretion, hyperinsulinemia, acutepancreatitis, GI cancers (especially cancers of the gall bladder andpancreas), motility disorders, pain (potentiation of opiate analgesia),central nervous system disorders such as anxiety, panic disorder,depression, neuroleptic disorders, tardive dyskinesia, Parkinson'sdisease, psychosis, including schizophrenia, or Gilles de la TouretteSyndrome; disorders of the appetite regulatory systems, bulimia,Zollinger-Ellison syndrome, and central G cell hyperplasia, and thetreatment of substance abuse.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptonate, glycerphosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, pictate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Also, the basic nitrogen-containing groups can be quaternized with suchagents as loweralkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides, and iodides; dialkyl sulfates, long chain halidessuch as decyl, lauryl, myristyl, and stearyl chlorides, bromides andiodides, arylalkyl halides like benzyl and phenethyl bromides, andothers. Water or oil-soluble or dispersible products are therebyobtained.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds of Formula I which contain a basic oracidic moiety by conventional methods. Generally, the salts are preparedby reacting the free base or acid with stoichiometric amounts or with anexcess of the desired salt forming inorganic or organic acid or base ina suitable solvent or various combinations of solvents.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids as HCI andphosphoric acid and such organic acids such as oxalic acid, maleic acid,succinic acid and citric acid. Other salts include salts with alkalimetals or alkaline earth metals, such as sodium, potassium, calcium, ormagnesium or with organic bases.

The pharmaceutically acceptable salts of the acid of Formula I are alsoreadily prepared by conventional procedures such as treating an acid ofFormula I with an appropriate amount of base, such as an alkali oralkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium,or magnesium, or an organic base such as an amine, e.g.,dibenzylethylenediamine, cyclohexylamine, dicyclohexylamine, TEA,piperidine, pyrrolidine, benzylamine, and the like, or a quateraryammonium hydroxide such as tetramethylammonium hydroxide and the like.

When a compound of Formula I is used as an antagonist of CCK or gastrinin a human subject, the total daily dose administered in single ordivided doses may be in amounts, for exan-tple, from 0.001 to 1000 mgaday and more usually 1 to 1000 mg. Dosage unit compositions may containsuch amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated, the particular treatment and the particular mode ofadministration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, rate of excretion,drug combination, and the severity of the particular disease undergoingtherapy.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleagenous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butandiol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,isotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsion, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The present agents can also be administered in the form of liposomes. Asis known in the art, liposomes are generally derived from phospholipidsor other lipid substances. Liposomes are formed by mono- ormulti-lamellar hydrated liquid crystals that are dispersed in an aqueousmedium. Any non-toxic, physiologically acceptable and metabolizablelipid capable of forming liposotnes can be used. The presentcompositions in liposome form can contain, in addition to the compoundsof the present invention, stabilizers, preservatives, excipients, andthe like. The preferred lipids are the phospholipids and thephosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Vol, XIV. Academic Press, NewYork, N.Y. 1976, p.33 et seq.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. A compound of the formula: ##STR8## or apharmaceutically-acceptable salt, ester or amide thereof, wherein: A isheteroaryl or substituted heteroaryl;B is absent, or is O, N, S,ethylene, or substituted ethylene; R¹ is hydrogen or C₁ -C₃ -alkyl; R²is:(1) hydrogen, (2) aryl-C₁ -C₃ -alkyl, or(3) when R³ is hydrogen,additionally C₁ -C₆ -alkyl, C₃ -C₇ -cycloalkyl, or C₂ -C₆ -alkenyl; orR² and D are linked together with the atoms to which they are attachedto form:(a) --C₄ -C₇ -alkylene, or (b) --(CH₂)_(q) -G-(CH₂)_(q) -,wherein q is independently 1, 2 or 3 at each occurrence and G is O or S;D is selected from the group consisting of:(1) hydrogen, (2) C₁ -C₆-alkyl, (3) C₂ -C₆ -alkenyl, (4) C₃ -C₇ -cycloalkyl, (5) aryl, (6)substituted aryl, (7) Het, (8) substituted Het, (9) aryl-C₁ -C₆ -alkyl-,(10) Het-C₁ -C₆ -alkyl-, (11) substituted Het-C₁ -C₆ -alkyl-, (12)aryl-(mono-substituted-C₁ -C₆ -alkyl)-, (13) Het-(mono-substituted-C₁-C₆ -alkyl)-, (14) R⁶ -O-C₁ -C₆ -alkyl-, wherein: R⁶ is:(i) hydrogen,(ii) C₁ -C₆ -alkyl, (iii) aryl-C₁ -C₆ -alkyl-, (iv) substituted aryl-C₁-C₆ -alkyl-, or (v) R⁷ --N--R⁸ --C(O)--, whereinR⁷ is: (a) C₁ -C₆-alkyl, (b) aryl, (c) substituted aryl, (d) Het, (e) aryl-C₁ -C₆-alkyl-, (f) substituted aryl-C₁ -C₆ -alkyl-, or (g) Het-C₁ -C₆ -alkyl-;and R⁸ is: (a) hydrogen, (b) C₁ -C₆ alkyl, (c) aryl, (d) substitutedaryl, or (e) aryl-C₁ -C₆ -alkyl-; or R⁷ and R⁸ may be linked togetherwith the atoms to which they are attached to form N--C₄ -C₇ -alkylene orN--(CH₂)_(q) --G--(CH₂)_(q) --, wherein q and G are as defined above;(15) R⁹ --S--C₁ -C₆ -alkyl-, wherein: R⁹ is:(i) C₁ -C₆ -alkyl, (ii) C₂-C₆ -alkenyl, (iii) aryl-C₁ -C₆ -alkyl-, (iv) substituted aryl-C₁ -C₆-alkyl-, or (v) R⁷ --N--R⁸ --C(O)--, wherein R⁷ and R⁸ are as definedabove; (16) R¹⁰ --S(O)_(n) -C₁ -C₆ -alkyl-,wherein: n is 1 or 2, and R¹⁰is C₁ -C₆ -alkyl-, aryl-C₁ -C₆ -alkyl-, or substituted aryl-C₁ -C₆-alkyl-; and (17) R¹¹ --NH--C₁ -C₆ -alkyl-, wherein: R¹¹ is:(i)hydrogen, (ii) N-protecting group, or (iii) R⁷ --J--CO--, wherein R⁷ isas defined above, and J is:(a) absent, (b) ethylene, (c) substitutedethylene, (d) O, (e) O--CH₂, (f) s, (f) S--CH₂, (h) NH, or (i) N(C₁ -C₃-alkyl); or (18) D is linked together with R² and atoms to which theyare attached to form C₄ -C₇ -alkylene or --(CH₂)_(q) -G-(CH₂)_(q) -,wherein q and G are as defined above; or (19) D is linked together withR³ and atoms to which they are attached to form --CO--N--C₃ -C₆-alkylene or --CO--N--(CH₂)_(q) --G--(CH₂)_(q) --, wherein q and G areas defined above; R³ is hydrogen or if R² or D is hydrogen, thenadditionally:(1) C₁ -C₆ -alkyl, (2) C₁ -C₃ -alkyl--O--C₁ -C₃ -alkyl, (3)C₂ -C₆ -alkenyl, (4) aryl-C₁ -C₆ -alkyl-, (5) C₃ -C₇ -cycloalkyl, or (6)--C₁ -C₆ -alkylene-CO₂ -R¹⁴, wherein R¹⁴ is C₁ -C₆ -alkyl or C₃ -C₇-cycloalkyl; or R³ and D may be linked together to form --CO--N--C₃ -C₅-alkylene or --CO--N--(CH₂)_(q) --G--(CH₂)_(q) --, wherein q and G areas defined above: R⁴ is selected from the group consisting of:(1) C₁ -C₃-alkyl, (2) C₁ -C₃ -alkyl-O--C₁ -C₃ -alkyl, (3) C₂ -C₄ -alkenyl, (4)aryl, (5) aryl-C₁ -C₆ -alkyl-, (6) C₃ -C₇ -cycloalkyl, (7) cyano-C₁ -C₆-alkyl, or (8) --C₁ -C₃ -alkylene-CO₂ -R¹⁴,wherein R¹⁴ is C₁ -C₆ -alkyl,C₃ -C₇ -cycloalkyl, aryl, or aryl- C₁ -C₆ -alkylene; or if R² ishydrogen, then R³ and R⁴ may be additionally linked to form: ##STR9##wherein: r is independently at each occurrence 1 or 2, Q is CH₂ or O,and R¹⁷ represents one or two substituents independently selected fromthe group consisting of:(1) hydrogen, (2) C₁ -C₆ -alkyl, (3) aryl, and(4) --C(O)--R¹⁸, wherein R¹⁸ is:(i) aryl, (ii) substituted aryl, (iii)heteroaryl, (iv) aryl-C₁ -C₃ -alkyl-, (v) substituted aryl-C₁ -C₃-alkyl, or (vi) N--R¹⁹ R²⁰, wherein: R¹⁹ is H or C₁ -C₃ alkyl, and R²⁰is aryl, aryl-C₁ -C₆ -alkyl-, or heteroaryl-C₁ -C₆ alkyl-.
 2. A compoundaccording to claim 1, whichis:N-(3'-Quinolylcarbonyl)-R-valine-di-n-pentylamide; N-(2'-Indolylcarbonyl)-R-valine-di-n-pentylamide;N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-valine-di-n-pentylamide;N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-valine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-norleucine-di-n-pentylamide;N-(2'-Indolylcarbonyl)-R-norleucine-di-n-pentylamide;N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-norleucine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-(O-benzyl)serine-di-n-pentylamide;N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-(O-benzyl)serine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-benzyl)threonine-di-n-pentylamide;N-(4'-Hydroxy-2'-quinolylcarbonyl)-(2R,3S)-(O-benzyl)threonine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-(2R,3S)-threonine-di-n-pentylamide;N-(4'-Hydroxy-2'-quinolylcarbonyl)-(2R,3S)-threonine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-methyl)threonine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-3-(2'-thienyl)-R-alanine-di-n-pentylamide;N-(4'-Hydroxy-2'-quinolylcarbonyl)-3-(2'-thienyl)-R-alanine-di-n-pentylamide;N-(2'-Indolylcarbonyl)-R-histidine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-histidine-di-n-pentylamide;N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-histidine-di-n-pentylamide; N^(a)-(3'-Quinolylcarbonyl)-N.sup.ε-(benzyloxycarbonyl)-R-lysine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-phenylalanine-di-n-pentylamide;N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-phenylalanine-di-n-pentylamide;N^(a) -(3'-Quinolylcarbonyl)-N.sup.ε-(2'-chiorobenzyloxycarbonyl)-R-lysine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-(4'-hydroxyphenyl)glycine-di-n-pentylamide;N.sup.α (3'-Quinolylcarbonyl)-N.sup.ε-(acetyl)-R-lysine-di-n-pentylamide:N-(2'-Indolylcarbonyl)-R-tyrosine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-tyrosine-di-n-pentylamide:N-(4'-Hydroxy-2'-quinolylcarbonyl)-R-tyrosine-di-n-pentylamide; MethylN-(3'-quinolylcarbonyl)-R-tyrosyl-S-phenylglycinate; MethylN-(4'-Hydroxy-2'-quinolylcarbonyl)-R-tyrosyl-S-phenylglycinate;N-(2'-Indolylcarbonyl)-R-homoserine-di-n-pentylamide;N-(3-Quinolylcarbonyl)-R-homoserine-di-n-pentylamide;N-(4-Hydroxy-2'-quinolylcarbonyl)-R-homoserine-di-n-pentylamide;N-(2-Indolylcarbonyl)-R-methionine-di-n-pentylamide;N-(2-Indolylcarbonyl)-R-methioninesulfoxide-di-n-pentylamide:N-(3-Quinolylcarbonyl)-R-methionine-di-n-pentylamide;N-(4-Hydroxy-2'-quinolylcarbony1)-R-methionine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-methioninesulfoxide-di-n-pentylamide; N^(a)-(3'-Quinolylcarbonyl)-N.sup.ε-phenylthiolcarbonyl-R-lysine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-tyrosine-di-n-pentylamide hydrochloride;N-(3'-Quinolylcarbonyl)-R-histidine-di-n-pentylamide dihydrochloride;N-(2'-Indolylcarbonyl)-glycine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-glycine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide;N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-Phenylglycine-di-n-pentylamide;N-(5'-Fluoroindolylcarbonyl)-R-phenylglycine-di-n-pentylamide:N-(5'-Chloroindolylcarbonyl)-R-phenylglycine-di-n-pentylamide:N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-glycine-di-n-pentylamide;N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-(4'-hydroxyphenyl)-glycine-di-n-pentylamide;N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-(2R,3S)-(O-benzyl)-threonine-n-pentylamide;MethylN-(2'-Indolylcarbonyl)-R-methionine-S-(p-hydroxy)-phenylglycinate;MethylN-(3'-Quinolylcarbonyl)-R-methionine-S-(p-hydroxy)-phenylglycinate;MethylN-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-methionine-S-(p-hydroxy)-phenylglycinate;N-(3'-Quinolylcarbonyl)-R-serine-di-n-pentylamide;N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-serine-di-n-pentylamide;N-(8'-Hydroxy-2-quinolylcarbonyl)-glycine-di-n-pentylamide;N-Methyl-N-(3'-quinolylcarbonyl)-glycine-di-n-pentylamide;N-(3'-Iodo-2'-indolylcarbonyl)-glycine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-alanine-di-n-pentylamide;N-(2'-Indolylcarbonyl)-R-alanine-di-n-pentylamide;N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-alanine-di-n-pentylamide; orN-(3'-Quinolylcarbonyl)-2-allyl-R,S-phenylalanine-n-pentylamide.
 3. Acompound according to claim 2, whichis:N-(3'-Quinolylcarbonyl)-(2R,3S)-(O-methyl)threonine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-(2R,3S)-threonine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-histidine-di-n-pentylamide dihydrochloride;N-(3'-Quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide;N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-phenylglycine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-serine-di-n-pentylamide; MethylN-(3'-quinolylcarbonyl)-R-tyrosyl-S-phenylglycinate;N-(3'-Quinolylcarbonyl)-R-(4'-hydroxyphenyl)glycine-di-n-pentylamide;N-(2'-Indolylcarbonyl)-R-histidine-di-n-pentylamide;N-(4',8'-Dihydroxy-2'-quinolylcarbonyl)-R-valine-di-n-pentylamide;N-(2'-Quinolylcarbonyl)-R-valine-di-n-pentylamide;N-(3'-Quinolylcarbonyl)-R-valine-di-n-pentylamide or.
 4. Apharmaceutical composition for antagonizing CCK comprising apharmaceutical carrier and a therapeutically-effective amount of acompound of claim
 1. 5. A pharmaceutical composition for treatment orprevention of anxiety, panic disorder, neuroleptic disorders,schizophrenia; or disorders of the gastrointestinal, appetite regulatingor pain regulating systems comprising a pharmaceutical carrier and atherapeutically-effective amount of a compound of claim
 1. 6. A methodfor treatment or prevention of anxiety, panic disorder, neurolepticdisorder, schizophrenia, or disorders of the gastrointestinal, appetiteregulating or pain regulating systems comprising administering to amammal in need of such treatment a therapeutically-effective amount of acompound of claim 1.